(chronic) - sofosbuvir [ID654]

Transcripción

CONFIDENTIAL UNTIL PUBLISHED
NATIONAL INSTITUTE FOR HEALTH AND CARE
EXCELLENCE
Final appraisal determination
Sofosbuvir for treating chronic hepatitis C
This guidance was developed using the single technology appraisal (STA) process.
1
Guidance
1.1
Sofosbuvir is recommended as an option for treating chronic hepatitis C in
adults, as specified in table 1.
Table 1 Sofosbuvir for treating adults with chronic hepatitis C
Genotype
Adults with
genotype 1
HCV
Adults with
genotype 2
HCV
Sofosbuvir in combination with
peginterferon alfa and ribavirin
Treatment
Recommendation
history
All
All
Recommended
Not licensed for
this population
ribavirin
Treatment
Recommendation
history
All
Not recommended
Treatmentnaive
Only
recommended
for people who
are intolerant to
or ineligible for
interferon
Treatmentexperienced
Recommended
Treatment-naive
Only
recommended for
people with
cirrhosis
Treatmentnaive
Recommended
Adults with
genotype 3
HCV
National Institute for Health and Care Excellence
Final appraisal determination – sofosbuvir for treating chronic hepatitis C
Issue date: January 2015
Only
recommended
for people with
cirrhosis who are
intolerant to or
ineligible for
interferon
Only
recommended
for people with
cirrhosis who are
intolerant to or
ineligible for
interferon
Page 1 of 104
peginterferon alfa and ribavirin
ribavirin
Treatment
Treatment
Genotype
Recommendation
Recommendation
history
history
Only
Adults with
recommended for
genotype 4, All
All
Not recommended
people with
5, or 6 HCV
cirrhosis
HCV – hepatitis C virus
Treatment-naive – the person has not had treatment for chronic hepatitis C
Treatment-experienced – the person’s hepatitis C has not adequately responded to
interferon-based treatment
1.2
People currently receiving treatment initiated within the NHS with
sofosbuvir that is not recommended for them by NICE in this guidance
should be able to continue treatment until they and their NHS clinician
consider it appropriate to stop.
2
The technology
2.1
Sofosbuvir (Sovaldi, Gilead Sciences) is a uridine nucleotide analogue
that inhibits hepatitis C virus (HCV) polymerase, preventing viral
replication. Sofosbuvir has a UK marketing authorisation for use ‘in
combination with other medicinal products for treating chronic hepatitis C
in adults’. The recommended dose is 1 daily 400 mg tablet, taken orally. It
should be used in combination with peginterferon alfa and ribavirin, or
ribavirin only, as stated in the summary of product characteristics.
Monotherapy with sofosbuvir is not recommended. The average duration
of treatment is 12 or 24 weeks depending on the person’s HCV genotype
and history of previous treatment with interferon. Combination treatment
regimens without peginterferon alfa for people with genotype 1, 4, 5 or 6
HCV infection have not been investigated in phase III studies. According
to the summary of product characteristics, treatment regimens without
peginterferon alfa should be used for people with genotype 1, 4, 5 or 6
infection only if they are intolerant to or ineligible for peginterferon alfa
therapy and are in urgent need of treatment. The summary of product
characteristics states that, for all genotypes, consideration should be
given to extending the duration of therapy from 12 to 24 weeks, especially
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for people who have 1 or more factors historically associated with lower
response rates to interferon-based therapies. These include people with
advanced liver fibrosis or cirrhosis, high baseline viral concentrations,
previous unresponsiveness to peginterferon alfa and ribavirin combination
therapy, or a single nucleotide polymorphism without 2 copies of the
C allele near their IL28B gene (that is, non-CC genotype IL28B
polymorphism); or for people of African and Caribbean family origin.
2.2
The summary of product characteristics lists the following most common
adverse reactions for sofosbuvir plus ribavirin, with or without
peginterferon alfa: fatigue, headache, nausea and insomnia. For full
details of adverse reactions and contraindications, see the summary of
product characteristics.
2.3
The cost of sofosbuvir is £11,660.98 per 28 tablet pack of 400 mg tablets
(excluding VAT, ‘British national formulary’ [BNF] May 2014). The cost of
a 12 week course of treatment is £34,982.94 and a 24 week course is
£69,965.88 (both excluding VAT), not including the cost for ribavirin and
peginterferon alfa. Costs may vary in different settings because of
negotiated procurement discounts.
3
The company’s submission
The Appraisal Committee (section 9) considered evidence submitted by
Gilead Sciences and a review of the submissions by the Evidence Review
Group (ERG; section 10).
3.1
The company provided clinical-effectiveness evidence, identified by
systematic review, consisting of 13 studies investigating the effect of
sofosbuvir plus ribavirin alone or ribavirin and peginterferon alfa in adults
with chronic hepatitis C. These included:
 Studies in people who have not had treatment for hepatitis C virus
(HCV) before (described as ‘treatment-naive’ in this document) with
genotype 1, 4, 5 or 6 HCV:
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 1 phase III open-label, single arm study (NEUTRINO, n=327)
 3 phase II randomised controlled trials (ATOMIC, n=332;
QUANTUM, n=50; SPARE, genotype 1 only, n=60).
 Studies in people with treatment-naive HCV or in people who have had
treatment before (described as ‘treatment-experienced’ in this
document) with genotype 2 and 3 HCV:
 4 phase III randomised controlled trials (FISSION, n=499 treatmentnaive; FUSION, n=201 treatment-experienced; POSITRON, n=278
treatment-naive and –experienced, people who had treatment before
were considered to be intolerant to interferon, ineligible for interferon
or unwilling to take it; VALENCE, n=419 treatment-naive and –
experienced)
 1 phase II open-label randomised controlled trial (ELECTRON, n=95
treatment-naive)
 1 phase II single-arm open-label study (LONESTAR-2, n=47
treatment-experienced)
 1 phase II 2-arm open-label single cohort study (PROTON, n=25
treatment-naive).
 1 phase II open-label 4 cohort study in people with genotype 1, 2 and 3
HCV and HIV co-infection (PHOTON-1, n=223).
 1 phase II open-label single-arm study in people with HCV waiting for a
liver transplant (P7977-2025, n=61).
People in the sofosbuvir trials were tested for cirrhosis using Fibrotest (a
biomarker test that uses the results of 6 blood serum tests to generate a
score correlating to the degree of liver damage) and Fibroscan (a noninvasive scan allowing the measurement of liver fibrosis based on its
elasticity). No liver biopsies were performed at study entry and therefore
liver fibrosis according to METAVIR score (which is based on liver biopsy
histology) was not available for the sofosbuvir trials.
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Evidence in people with genotype 1, 4, 5 or 6 HCV
Treatment-naive population
3.2
NEUTRINO compared the efficacy and safety of sofosbuvir plus
peginterferon alfa and ribavirin for 12 weeks in people with genotype 1, 4,
5, or 6 treatment-naive chronic HCV with a historical control. The primary
outcome was sustained virological response 12 weeks after the end of
treatment. The study did not include sites in the UK. A historical control
rate of 60% for sustained virological response was used for peginterferon
alfa-2a and ribavirin, taken from the phase III telaprevir (ADVANCE) and
boceprevir (SPRINT2) trials. The people in the study had a median age of
54 years (age range 19 to 70 years); 64% were men; 78% had baseline
HCV RNA greater than 6 log10 IU/ml (viral load, or the number of virus
particles in the blood; a viral load less than 6 log10 IU/ml has been linked
to better response to treatment); 17% had cirrhosis; 89% had genotype 1
HCV and 11% had genotype 4, 5 or 6 HCV.
3.3
Results from the NEUTRINO study showed that 12 weeks after the end of
treatment with sofosbuvir plus peginterferon alfa and ribavirin, 90%
(95% confidence interval [CI] 87 to 93%, p<0.001) of people with
genotype 1, 4, 5, or 6 treatment-naive HCV had a sustained virological
response. Cirrhosis and non-CC IL28B polymorphism were both
associated with a reduced sustained virological response at 12 weeks:
92% (95% CI 89 to 95%) for people without cirrhosis, 80% (95% CI 67 to
89%) for those with cirrhosis (p=0.0018), and 98% (95% CI 93 to 100%)
for people with the IL28B CC genotype polymorphism compared with 87%
(95% CI 82 to 91%) for those with the non-CC IL28B polymorphism
(p=0.006). Sustained virological response at 12 weeks was 90% for
people with genotype 1 HCV. Overall, the sustained virological response
at 12 weeks was 97% for people with genotype 4, 5 or 6 HCV (100% in
the 33 people without cirrhosis, and 50% in the 2 people with cirrhosis).
No patient had a relapse during treatment. Relapse after virological
response at the end of treatment occurred in 28 of 327 people after
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stopping treatment; 25 completed 12 weeks of treatment and 3 did not
complete the treatment course. The company did not provide any
information about the family origin of people in the NEUTRINO study.
3.4
ATOMIC compared the efficacy and safety of sofosbuvir plus
peginterferon alfa and ribavirin in people with genotype 1, 4, 5 or 6
treatment-naive chronic HCV. The study included 3 treatment arms: 1 arm
had sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks, the
second arm had the same treatment for 24 weeks, and the third arm had
the same treatment for 12 weeks, followed by 12 weeks of sofosbuvir
monotherapy (sofosbuvir monotherapy is outside of the marketing
authorisation for sofosbuvir, but the results were included by the company
for information). The primary outcome was sustained virological response
24 weeks after the end of treatment. Most people had genotype 1 HCV,
and no one with genotype 5 HCV was enrolled in the study. Results
showed that after treatment with sofosbuvir, sustained virological
responses of 96–98% were achieved in each treatment arm. This
suggests that for sofosbuvir plus peginterferon alfa and ribavirin treatment
there is no increase in sustained virological response when treatment is
extended beyond 12 weeks.
3.5
QUANTUM compared the efficacy and safety of sofosbuvir plus ribavirin
for 12 weeks with 24 weeks of treatment in people with genotype 1, 4, 5 or
6 treatment-naive chronic HCV. The primary outcome was sustained
virological response 12 weeks after the end of treatment, which was 56%
(n=25) for people who had 12 weeks of sofosbuvir plus ribavirin and 52%
(n=25) for people who had 24 weeks of sofosbuvir plus ribavirin. Results
showed no statistically significant difference between treatment arms.
3.6
SPARE was a 2 part study that investigated the efficacy and safety of
sofosbuvir plus ribavirin treatment for 24 weeks in people with genotype 1
treatment-naive chronic HCV. The first part was a 1 arm open-label study
of the efficacy and safety of sofosbuvir plus ribavirin treatment for
24 weeks. The second part investigated 24 weeks of sofosbuvir plus
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ribavirin (using the licensed weight-based dose) compared with sofosbuvir
plus a low, unlicensed dose of ribavirin. The primary outcome was
sustained virological response 24 weeks after the end of treatment. In
part 1 of the study, sustained virological response was achieved in 90%
(n=9) of people. In part 2, 24 people in each group (96%) had viral
suppression by week 4 of treatment. However after completing treatment,
7 people in the weight-based ribavirin group and 10 people in the lowdose ribavirin group had a relapse. The sustained virological response
12 weeks after the end of treatment in the intention-to-treat population
was 68% (n=25) for people having 24 weeks of sofosbuvir plus weightbased ribavirin and 48% (n=25) for people having 24 weeks of sofosbuvir
plus low-dose ribavirin. The sustained virological response 24 weeks after
the end of treatment was the same as the response 12 weeks after the
end of treatment.
Treatment-experienced population
3.7
The company did not provide any evidence for the efficacy of sofosbuvir
plus ribavirin, or sofosbuvir plus peginterferon alfa and ribavirin in people
with genotype 1, 4, 5 or 6 treatment-experienced chronic HCV.
Evidence in people with genotype 2 or 3 HCV
Treatment-naive population
3.8
FISSION compared sofosbuvir plus ribavirin for 12 weeks with
peginterferon alfa-2a plus ribavirin treatment for 24 weeks in people with
genotype 2 or 3 treatment-naive chronic HCV. The primary outcome was
sustained virological response 12 weeks after the end of treatment. The
non-inferiority of sofosbuvir plus ribavirin compared with peginterferon
alfa-2a plus ribavirin for sustained virological response at 12 weeks
(primary end point) was tested. People in the study were randomised in a
1:1 ratio and stratified by the presence or absence of cirrhosis, HCV
genotype (2 or 3) and baseline HCV RNA level (<6 log10 IU/ml or
≥6 log10 IU/ml). The people in the study had a median age of 50 years
(range from 19 to 77 years); 66% were men; 57% had baseline HCV RNA
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levels greater than 6 log10 IU/ml; 20% had cirrhosis; 72% had genotype 3
HCV.
3.9
Results from FISSION showed that at 12 weeks after the end of
treatment, sustained virological response was 67% in both treatment
groups. Sofosbuvir plus ribavirin was non-inferior to peginterferon alfa-2a
plus ribavirin for the primary end point. The absolute difference between
treatment groups after adjusting for stratification was 0.3% (95% CI −7.5%
to 8.0%, non-inferiority p<0.001). HCV genotype and cirrhosis were
associated with differences in sustained virological response (see table 2).
Table 2 Sustained virological response 12 weeks after the end of treatment
from FISSION
Percentage of people with a sustained virological response
12 weeks after end of treatment (95% CI)
HCV genotype
Sofosbuvir plus ribavirin
Peginterferon alfa-2a plus
ribavirin
2
97% (90 to 100%), (n=70)
78% (66 to 87%), (n=67)
3
56% (48 to 63%), (n=183)
63% (55 to 70%), (n=176)
2 or 3 without cirrhosis
72% (65 to 78%), (n=206)
74% (67 to 80%), (n=193)
2 or 3 with cirrhosis
47% (33 to 62%), (n=50)
38% (25 to 53%), (n=50)
2 without cirrhosis
98.3%*, (n=59)
81.5 %*, (n=54)
2 with cirrhosis
90.9%*, (n=11)
61.5 %*, (n=13)
3 without cirrhosis
61%*, (n=145)
71%*, (n=139)
3, with cirrhosis
34%*, (n=38)
30%*, (n=37)
*Confidence intervals not reported, HCV; hepatitis C virus
3.10
ELECTRON was carried out in 2 centres in New Zealand. The study
included 8 treatment arms, only 5 of which were used by the company to
inform its submission. The treatment arms presented included people with
genotype 1, 2 and 3 treatment-naive chronic HCV who had sofosbuvir
plus ribavirin with or without peginterferon alfa-2a. In 4 of the treatment
arms, people with genotype 2 or 3 HCV had sofosbuvir plus ribavirin for
12 weeks and either 0, 4, 8 or 12 weeks of peginterferon alfa-2a. In
another treatment arm, added as a protocol amendment after the
4 previous dose-ranging treatment arms were completed, people with
genotype 2 or 3 HCV had sofosbuvir plus peginterferon alfa-2a and
Page 8 of 104
ribavirin for 8 weeks. Across the 5 study arms that were included in the
company’s submission, 100% of people with genotype 2 or 3 HCV had a
sustained virological response 12 weeks after the end of treatment.
3.11
PROTON was a study in 22 centres in the USA in which people with
genotype 1, 2 and 3 treatment-naive chronic HCV had sofosbuvir plus
peginterferon alfa-2a and ribavirin. The company only presented results
from the study arm that included people with genotype 2 or 3 HCV, who
had sofosbuvir plus peginterferon alfa-2a and ribavirin for 12 weeks,
because the other study arm was not used to inform its regulatory
submission. Results from PROTON showed that sustained virological
response 12 weeks after the end of treatment was 92% (no confidence
interval reported in company’s submission) across both genotypes, and
93% in people with genotype 2 HCV and 90% in people with genotype 3
HCV.
Treatment-experienced population
3.12
FUSION compared the efficacy and safety of sofosbuvir plus ribavirin for
either 12 or 16 weeks in people with genotype 2 or 3 chronic HCV, whose
disease had no response to previous HCV treatment (25%), or had lost its
initial response during or after previous HCV treatment (75%). The study
did not include sites in the UK. The people in the study had a median age
of 56 years (range 24 to 70 years); 70% were men; 73% had baseline
HCV RNA levels greater than 6 log10 IU/ml; 34% had cirrhosis; 63% had
genotype 3 HCV.
3.13
Results from FUSION showed that HCV genotype and cirrhosis were
associated with differences in sustained virological response (see table 3).
from FUSION
HCV genotype
2 or 3
12 weeks after end of treatment
Sofosbuvir plus ribavirin for Sofosbuvir plus ribavirin for
12 weeks
16 weeks
50% (95%CI 40 to 60%),
73% (95% CI 63 to 81%),
Page 9 of 104
(n=100)
2
86%*, (n=36)
3
30%*, (n=64)
2 without cirrhosis
96%*, (n=26)
2 with cirrhosis
60%*, (n=10)
3 without cirrhosis
37%*, (n=38)
3 with cirrhosis
19%*, (n=26)
3.14
(n=95)
94%*, (n=32)
62%*, (n=63)
100%*, (n=23)
78%*, (n=9)
63%*, (n=40)
61%*, (n=23)
LONESTAR-2 evaluated the efficacy and safety of sofosbuvir plus
peginterferon alfa-2a and ribavirin for 12 weeks in people with genotype 2
or 3 chronic HCV, whose disease had no response to previous HCV
treatment (15%), or had lost its initial response during or after previous
HCV treatment (85%). The study included 1 site in the USA. The people in
the study had a median age of 56 years (age range 39 to 72 years); 68%
were men; the mean baseline HCV RNA level was 6.2 log10 IU/ml (range
from 4.0 to 7.2 log10 IU/ml); 55% had cirrhosis; 51% had genotype 3 HCV.
3.15
Results from LONESTAR-2 showed that sustained virological response
12 weeks after the end of treatment was 89% (no confidence intervals
were reported in the company’s submission) in people with genotype 2 or
3 HCV. HCV genotype and cirrhosis were not associated with statistically
significant differences in sustained virological response. At 12 weeks after
the end of treatment, sustained virological response was 96% and 83% in
people with genotype 2 and genotype 3 HCV respectively. In people with
genotype 2 HCV without cirrhosis, sustained virological response at
12 weeks after the end of treatment was 100% and in people with
cirrhosis it was 93%. In people with genotype 3 HCV, the sustained
virological response was 83% for people with and without cirrhosis.
Treatment-naive or treatment-experienced
3.16
VALENCE was an unblinded study in which all people with genotype 2
HCV had sofosbuvir plus ribavirin for 12 weeks, and those with
genotype 3 HCV had sofosbuvir plus ribavirin for 24 weeks. Because of
changes made during the study, 11 people with genotype 3 HCV had a
Page 10 of 104
12 week course of therapy. As a result of emerging data showing that
people with genotype 3 HCV had higher sustained virological responses
when they were treated for longer, treatment for all people with
genotype 3 in the study was extended to 24 weeks and the goals of the
study were redefined to be descriptive and not include hypothesis testing.
People in the study had a median age of 51 years (range 19 to 74 years);
60% were men; the mean baseline HCV RNA level was 6.4 log10 IU/ml;
21% had cirrhosis; 78% had genotype 3 HCV. In around 65% of people
with treatment-experienced HCV, initial response was lost during or after
previous treatment, 30% had no response to interferon-based treatment,
and 5% were intolerant to interferon.
3.17
Results from VALENCE showed that sustained virological response
12 weeks after the end of treatment for people with genotype 2 HCV
having sofosbuvir plus ribavirin for 12 weeks was 93% (no confidence
intervals were reported in company’s submission). In people with
genotype 3 HCV who were treated for 24 weeks, the sustained virological
response 12 weeks after the end of treatment was 84% overall, and 93%
in people who had never been treated and 77% in people who had been
previously treated (no confidence intervals for this study were reported in
the company’s submission).
Population for whom interferon treatment was unsuitable (treatment-naive and
treatment-experienced)
3.18
POSITRON evaluated the efficacy and safety of sofosbuvir plus ribavirin
compared with placebo for 12 weeks in people with genotype 2 or 3 HCV.
People in the study had previously discontinued interferon therapy owing
to unacceptable adverse events (the company referred to this group as
interferon intolerant), or had a concurrent medical condition preventing
therapy with an interferon-containing regimen (the company referred to
this group as interferon ineligible), or were unwilling to have interferon
treatment. Similar proportions of people with genotype 2 and 3 HCV were
enrolled (51% and 49% respectively) in the study. People were
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randomised in a 3:1 ratio to receive sofosbuvir plus ribavirin or placebo,
and were stratified (grouped) by the presence or absence of cirrhosis. The
difference in sustained virological response 12 weeks after the end of
treatment was assessed for superiority, which was demonstrated if the pvalue was less than 0.05. People treated in the study had a median age of
54 years (range 21 to 75 years); 54% were men; 70% had baseline
HCV RNA levels greater than 6 log10 IU/ml; 16% had cirrhosis. The
proportions of people who were intolerant to interferon, ineligible for
interferon, or unwilling to have it were 9%, 44%, and 47% respectively.
Most people had not had previous treatment for chronic hepatitis C
(81.3%).
3.19
Results from POSITRON showed that HCV genotype and cirrhosis were
associated with differences in sustained virological response in people
treated with sofosbuvir plus ribavirin (see table 4). The difference in
sustained virological response between the sofosbuvir plus ribavirin and
the placebo group was statistically significant (p<0.001) for people with
genotype 2 or 3 chronic HCV.
from POSITRON
12 weeks after end of treatment
HCV genotype
Sofosbuvir plus ribavirin for
Placebo
12 weeks
2 or 3
78% (95%CI 72 to 83%), (n=207) 0%, (n=71)
2
93%*, (n=109)
3
61%*, (n=98)
2 without cirrhosis
92%*, (n=92)
2 with cirrhosis
94%*, (n=17)
3 without cirrhosis
68%*, (n=84)
3 with cirrhosis
21%* (n=14)
Page 12 of 104
People with HIV and HCV co-infection
3.20
The safety and efficacy of 12 or 24 weeks of treatment with sofosbuvir
plus ribavirin in people with genotype 1, 2 or 3 chronic hepatitis C who
were co-infected with HIV was evaluated in an open-label clinical study
(PHOTON-1). People in the study had genotype 2 or 3 treatment-naive or
treatment-experienced HCV or genotype 1 treatment-naive HCV. People
with genotype 2 or 3 treatment-naive HCV had sofosbuvir plus ribavirin for
12 weeks. People with genotype 2 or 3 treatment-experienced HCV and
people with genotype 1 treatment-naive HCV had sofosbuvir plus ribavirin
for 24 weeks. Participants were either not on antiretroviral therapy with a
CD4+ cell count above 500 cells/mm3 or had virologically suppressed
HIV-1 with a CD4+ cell count above 200 cells/mm3. At the time of
enrolment, 95% of participants had antiretroviral therapy. Preliminary
sustained virological response at 12 weeks was available for 210 people.
3.21
Results from PHOTON-1 showed that treatment with sofosbuvir plus
ribavirin for 12 weeks in people with genotype 1, 2 or 3 HCV and HIV coinfection and 24 weeks in people with genotype 1, 2 or 3 HCV and HIV coinfection resulted in sustained virological response at 12 weeks after
treatment irrespective of HCV genotype (≥93%; interim analysis). Similar
safety and tolerability profiles were reported in people with HIV and HCV
co-infection and in people with HCV only.
People awaiting liver transplant
3.22
An open-label clinical study (P7977-2025) was carried out in people with
chronic hepatitis C awaiting a liver transplant. It evaluated the safety and
efficacy of sofosbuvir plus ribavirin administered before transplant to
prevent post-transplant HCV reinfection. The primary end point of the
study was post-transplant virological response (HCV RNA undetectable at
12 weeks after transplant). People with HCV regardless of genotype, with
hepatocellular carcinoma suitable for liver transplant, had 400 mg
sofosbuvir and 1000–1200 mg ribavirin daily for a maximum of 24 weeks.
This was subsequently amended to 48 weeks or until the time of liver
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transplant, whichever was first. An interim analysis of results for 61 people
who had sofosbuvir and ribavirin, most of whom had genotype 1 HCV,
showed that 44 had a liver transplant up to 48 weeks after treatment with
sofosbuvir and ribavirin and 41 had no detectable HCV RNA at the time of
their transplant. Results suggested that treatment with sofosbuvir and
ribavirin prevented HCV recurrence in 64% of people compared with a
100% historical risk of reinfection without prophylaxis. During treatment,
HCV RNA suppression in people with well-compensated cirrhosis awaiting
a liver transplant for hepatocellular carcinoma was rapid and similar to
that seen in other patient populations treated with sofosbuvir regimens.
Adverse effects of treatment
3.23
The company presented data on adverse events for NEUTRINO,
FISSION, FUSION, POSITRON and VALENCE. The most common
adverse events among people receiving sofosbuvir and ribavirin therapy
(with or without peginterferon alfa) were fatigue, headache, anaemia,
nausea, insomnia, irritability, rash, pruritis, myalgia, decreased appetite,
influenza-like illness, chills, pyrexia, and neutropenia. Of these events,
fatigue and headache were usually the most frequent, affecting more than
40% of the people in some studies.
Health-related quality of life
3.24
The company assessed health-related quality of life during the phase II
and III trials using the Chronic Liver Disease Questionnaire – Hepatitis C
(CLDQ-HCV), the Functional Assessment of Chronic Illness TherapyFatigue measurement system (FACIT-F), the Work Productivity and
Activity Impairment questionnaire (WPAI), or the Short Form-36 items
survey (SF-36). People in the phase III trials were not aware of their
sustained virological response when completing the quality-of-life
questionnaires. The results from NEUTRINO showed that there were
differences in health-related quality of life scores between baseline and
the end-of-treatment and that scores returned to baseline values by the
post-treatment week 12 visit. The results from the FISSION study
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indicated that health-related quality of life during treatment in people who
had peginterferon alfa-2a plus ribavirin was statistically significantly lower
than for people in the sofosbuvir plus ribavirin arm. No difference was
seen between the arms 12 weeks after the end of each treatment. The
CLDQ-HCV results from FUSION indicated that health-related quality of
life scores did not decrease significantly in either treatment group and
there were no statistically significant differences in overall scores between
the groups. The health-related quality of life data obtained from
POSITRON showed decreases (worsening) in all SF-36 scales and the
Mental Component and Physical Component scores in both treatment
groups during treatment (baseline through to week 12). In the sofosbuvir
plus ribavirin group the differences were statistically significant (p<0.001)
from baseline in the Physical Function scale, Role Physical, Vitality, Social
Functioning, Role Emotional, and Mental Health scales; however, there
were no statistically significant differences from placebo at any time point.
Mixed treatment comparison
3.25
The company carried out a mixed treatment comparison to explore the
comparative data for sofosbuvir and other relevant comparators. Because
of limited data, a mixed treatment comparison network could not be
formed for all the relevant populations in the decision problem and the
comparison was done only for people with genotype 1, 2 or 3 treatmentnaive HCV for whom interferon therapy was suitable. In addition, the
company’s economic model required that efficacy data were split by
cirrhosis status and these data were not available for all trials. In people
with genotype 1 HCV, a network including sofosbuvir was possible only by
linking 2 small phase II trials (ATOMIC and PROTON) which included only
people without cirrhosis. In people with genotype 2 or 3 HCV, the mixed
treatment comparison results were based on people with and without
cirrhosis combined. The results of the mixed treatment comparison
showed that for people with genotype 1 treatment-naive HCV regardless
of cirrhosis status, 84.9% of those who had sofosbuvir plus peginterferon
alfa and ribavirin for 12 weeks had a sustained virological response at
Page 15 of 104
12 weeks after treatment, compared with 46.2% of people who had
peginterferon alfa and ribavirin for 48 weeks, 76.5% of people who had
telaprevir plus peginterferon alfa and ribavirin and 69.7% of people who
had boceprevir plus peginterferon alfa and ribavirin. For people with
genotype 2 treatment-naive HCV without cirrhosis, 98.6% of those who
had sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks had a
sustained virological response at 12 weeks after treatment, compared with
85.6% of people who had peginterferon alfa and ribavirin for 24 weeks.
For people with genotype 2 treatment-naive HCV with cirrhosis, sustained
virological response was achieved in 97.5% of people who had sofosbuvir
and ribavirin for 12 weeks, and in 67.5% of those who had peginterferon
alfa and ribavirin for 24 weeks. For people with genotype 3 treatmentnaive HCV without cirrhosis for whom interferon therapy was suitable,
62% of those who had sofosbuvir plus ribavirin for 12 weeks had a
sustained virological response at 12 weeks after treatment, compared with
68.3% of people who had peginterferon alfa and ribavirin for 24 weeks.
For people with genotype 3 treatment-naive HCV with cirrhosis who had
sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa and ribavirin for
24 weeks, the sustained virological response was similar (47.8% and
42.8% respectively) between the 2 treatment groups. The company
highlighted several limitations to its mixed treatment comparison including
the fact that the 12-week sofosbuvir plus ribavirin regimen used to treat
genotype 3 HCV is not licensed. Therefore, the company stated that the
results of the mixed treatment comparison could not be considered robust.
Evidence Review Group comments
3.26
The ERG reviewed the clinical evidence in the company’s submission. It
considered that the company’s interpretation of the clinical evidence was
overall justified and unbiased. However, the ERG cautioned that most of
the evidence provided did not directly address the decision problem,
because of the lack of head-to-head studies against current standard of
care comparators. In addition, it highlighted that no studies were included
that examined the efficacy of sofosbuvir within its marketing authorisation
Page 16 of 104
for people with genotype 1 treatment-experienced HCV. The ERG also
noted that some of the evidence from VALENCE supporting the treatment
regimens licensed for use in people with genotype 3 HCV should be
interpreted with caution because randomisation was broken during the
study, and some people were switched from 12 to 24 weeks of treatment
with sofosbuvir plus ribavirin.
3.27
The ERG noted that the company only included adverse events from the
5 phase III studies (NEUTRINO, FISSION, FUSION, POSITRON and
VALENCE). However, the ERG confirmed that the adverse events in the
phase II studies were similar to those in the phase III studies. Overall, the
ERG was satisfied that the evidence showed that treatment with
sofosbuvir-based regimens was generally well tolerated and led to fewer
adverse events than treatment with peginterferon alfa and ribavirin.
Cost effectiveness
3.28
The company identified 112 cost-effectiveness studies of chronic
hepatitis C treatments. No studies were identified that compared
sofosbuvir with alternative treatments.
3.29
To assess the cost effectiveness of sofosbuvir the company submitted a
multi-state Markov model, which compared sofosbuvir plus ribavirin and
sofosbuvir plus peginterferon alfa and ribavirin with the comparators
defined in the decision problem (that is, boceprevir or telaprevir plus
peginterferon alfa and ribavirin for people with genotype 1 HCV, and
peginterferon alfa and ribavirin or placebo for people with other HCV
genotypes). The structure of the model was based on published health
economic models, but was amended by the company to reflect the data
available from its pivotal clinical trials and only distinguished between
people with and without cirrhosis. The company used patient
characteristics from the HCV UK research database to inform the
population entering the model, including mean age at start of treatment,
disease severity distribution and weight. The model had a total of 9 health
states according to disease stage and treatment response. People
Page 17 of 104
entered the model in either the non-cirrhotic or compensated cirrhosis
stages of disease. People who had antiviral treatment could move into the
non-cirrhotic or sustained virological response cirrhotic health states.
Those who did not clear the virus after treatment remained in their
respective health states, or progressed to more severe stages of chronic
HCV. All patients in the decompensated cirrhosis health state were
assumed to be candidates for liver transplant. The model assumed that
people who have a sustained virological response will not progress to
more severe health states during or after therapy. Reversion to less
severe health states was not permitted if treatment was unsuccessful.
3.30
The company applied age-specific general population mortality rates to
each health state in the model. The same model structure was used for all
patients irrespective of HCV genotype or treatment experience. For the
first 2 years a 3-month cycle was used in the model, then the remaining
cycles each lasted 1 year. A half-cycle correction was applied, which is
consistent with previous hepatitis C appraisals. An NHS and personal and
social services perspective was taken and a lifetime horizon was used,
with costs and outcomes discounted at 3.5%.
3.31
Data from clinical trials were used to inform model inputs for treatment
effects, health-related quality of life and adverse events. Treatment effect
data were based on the sustained virological responses taken from the
sofosbuvir clinical trials. If data for comparators were not available in
these trials, they were taken from other published studies identified by the
company. The company collected quality-of-life scores at baseline,
week 12 during treatment, and at 4, 12 and 24 weeks after treatment. The
SF-36 quality of life data were converted to SF-6D utility data and used in
the company’s base case. The company also converted SF-36 data to the
EQ-5D and incorporated these in a deterministic sensitivity analysis.
Adverse event rates were obtained from the sofosbuvir clinical trials and
published studies. The company incorporated the rates of grade 3 and 4
pruritus, diarrhoea and nausea, vomiting, rash, anaemia,
thrombocytopenia, neutropenia, and depression from the trials into the
Page 18 of 104
model so that drug acquisition costs could be included for interventions
associated with managing these adverse events.
3.32
The company used transition probabilities for disease progression from
2 published UK health technology assessments and 1 UK study: Hartwell
et al. (2011), Shepherd et al. (2007), and Grishchenko et al. (2009), which
used estimates from the Trent database (a large sample of people with
HCV who attended only non-tertiary centres in the UK).
3.33
Utility values estimated from the sofosbuvir clinical studies were not used
to inform the model. Instead, the company used utility values from
previous technology appraisals for hepatitis C treatments that were based
on the UK trial of mild chronic hepatitis C by Wright et al. (2006). The
company calculated treatment-related utilities by applying treatmentrelated utility decrements to the baseline utility estimates.
3.34
The company compared sofosbuvir plus ribavirin (with or without
peginterferon alfa), telaprevir plus peginterferon alfa and ribavirin,
boceprevir plus peginterferon alfa and ribavirin, peginterferon alfa plus
ribavirin, and best supportive care. Sofosbuvir, telaprevir, boceprevir,
peginterferon alfa-2a and ribavirin were used in the model according to
their marketing authorisations. The company applied no stopping rules,
lead-in phase, or option for sofosbuvir retreatment, in line with the
sofosbuvir clinical trials.
3.35
The company used costs in the model that reflected the UK NHS
perspective, comprising treatment-related costs (drug acquisition and
patient monitoring), health-state costs and adverse event costs. Drug
costs were based on the list price in the BNF (June 2013). Costs for drugs
used to treat adverse events in the model were taken from the BNF. The
company used the BNF price of ribavirin (Copegus 400 mg, 56 tablet
packs) at a cost of £246.65 in the model. Costs for the health states in the
model were identified using published sources taken from the resource
and costs systematic review done by the company. The costs for the non-
Page 19 of 104
cirrhotic health state were based on a calculation of the costs associated
with mild and moderate cirrhosis (Wright et al.) using an assumed 77%:
23% split between mild and moderate cirrhosis. Costs were inflated to
2011/12 prices (using the Hospital and Community Health Service pay
and prices index).
3.36
Monitoring costs included resource unit costs of outpatient appointments,
inpatient care, tests and investigations (virology, pathology, haematology,
immunology, radiology) and procedures (liver biopsy). The source for
monitoring costs was the National Schedule of Reference Costs,
published studies or expert opinion.
Results
3.37
The company presented base-case analyses for sofosbuvir plus ribavirin
with or without peginterferon alfa compared with current standard of care,
based on HCV genotype, interferon eligibility and treatment history. The
company’s results show that sofosbuvir treatment regimens increased the
cost of treatment, but were associated with more quality-adjusted life
years (QALYs) gained, a greater probability of sustained virological
response (cure), and a reduction in end-stage liver disease and death.
Genotype 1
3.38
For, people with genotype 1 treatment-naive HCV for whom interferon
therapy was suitable, the company’s base-case analysis showed that the
incremental cost-effectiveness ratio (ICER) for sofosbuvir plus
peginterferon alfa and ribavirin treatment for 12 weeks compared with
peginterferon alfa and ribavirin treatment for 48 weeks was £14,930 per
QALY gained (incremental cost £19,129; incremental QALYs 1.3).
Boceprevir plus peginterferon alfa and ribavirin was dominated (that is,
sofosbuvir plus peginterferon alfa and ribavirin was less expensive and
more effective) and telaprevir plus peginterferon alfa and ribavirin was
extendedly dominated (that is, its ICER is higher than that of the next,
more effective option when compared with a common baseline). For
people with genotype 1 treatment-naive HCV for whom interferon therapy
Page 20 of 104
was not suitable, the company’s base-case ICER for sofosbuvir plus
ribavirin for 24 weeks compared with no treatment was £49,249 per QALY
gained (incremental cost £63,903; incremental QALYs 1.3).
3.39
The company did not do an economic analysis for genotype 1 treatmentexperienced HCV because there was no clinical evidence available to
populate the economic model for this population. However, an economic
analysis for genotype 1 treatment-experienced HCV was later provided by
the company (see section 3.69).
Genotype 2
3.40
In people with genotype 2 treatment-naive HCV for whom interferon
therapy was suitable, the company’s base-case ICER for sofosbuvir plus
ribavirin treatment for 12 weeks compared with peginterferon alfa and
ribavirin treatment for 24 weeks was £46,324 per QALY gained
(incremental cost £27,779; incremental QALYs 0.6). In people with
genotype 2 treatment-naive HCV for whom interferon therapy was not
suitable, the company’s base-case ICER for sofosbuvir plus ribavirin for
12 weeks compared with no treatment was £8154 per QALY gained
(incremental cost £20,051; incremental QALYs 2.5).
3.41
In people with genotype 2 treatment-experienced HCV for whom
interferon therapy was suitable, the company’s base-case ICER for
sofosbuvir plus ribavirin treatment for 12 weeks compared with
peginterferon alfa and ribavirin treatment for 48 weeks was £9274 per
QALY gained (incremental cost £21,498; incremental QALYs 2.3). In
people with genotype 2 treatment-experienced HCV for whom interferon
therapy was not suitable, the company’s base-case ICER for sofosbuvir
and ribavirin treatment for 12 weeks compared with no treatment was
£8591 per QALY gained (incremental cost £20,697; incremental
QALYs 2.4).
Page 21 of 104
Genotype 3
3.42
therapy was suitable, the company’s base-case ICER for sofosbuvir plus
QALY gained (incremental cost £24,970; incremental QALYs 1.2). In
was not suitable, the company’s base-case ICER for sofosbuvir plus
gained (incremental cost £55,137; incremental QALYs 2.6).
3.43
interferon therapy was suitable, the company’s base-case ICER for
sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks
compared with peginterferon alfa and ribavirin treatment for 48 weeks was
£8557 per QALY gained (incremental cost £19,634; incremental
QALYs 2.3). In people with genotype 3 treatment-experienced HCV for
whom interferon therapy was not suitable, the company’s base-case ICER
for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was
£28,569 per QALY gained (incremental cost £58,828; incremental
QALYs 2.1).
Genotypes 4, 5 or 6
3.44
In people with genotype 4, 5 or 6 treatment-naive HCV for whom
interferon therapy was suitable, the company’s original base-case ICER
for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks
£26,797 per QALY gained (incremental cost £23,942; incremental
QALYs 0.9). In sensitivity analyses, the sustained virological response for
peginterferon alfa plus ribavirin for 48 weeks (which varied between
26.6% and 73.4%) had a large impact on the cost-effectiveness results.
3.45
The company tested the robustness of the model using deterministic
sensitivity analyses. Results showed that the ICERs were most sensitive
Page 22 of 104
to changes in the discount rate (varied between 0% and 6% for costs and
outcomes simultaneously) and the utility increment after achieving a
sustained virological response. The company concluded that the results of
the deterministic sensitivity analyses showed that the ICERs for
sofosbuvir remained below £20,000 per QALY gained in the following
subgroups:
 people with genotype 2 treatment-naive and treatment-experienced
HCV, for whom interferon treatment is unsuitable, compared with no
treatment
 people with genotype 2 and 3 treatment-experienced HCV, for whom
interferon therapy is suitable, compared with no treatment.
The results of the deterministic sensitivity analyses showed that the
ICERs for sofosbuvir were between £20,000 and £30,000 per QALY
gained in the following subgroups:
 people with genotype 1 treatment-naive HCV, for whom interferon
therapy is suitable, compared with peginterferon alfa and ribavirin and
boceprevir plus peginterferon alfa and ribavirin
 people with genotype 2 treatment-experienced HCV, for whom
interferon therapy is suitable, compared with peginterferon alfa and
ribavirin
 people with genotype 3 treatment-experienced HCV, for whom
interferon therapy is suitable, compared with peginterferon alfa and
ribavirin.
The results of the deterministic sensitivity analyses showed that the
ICERs for sofosbuvir were above £30,000 per QALY gained in the
following subgroups:
therapy is suitable, compared with telaprevir plus peginterferon alfa and
ribavirin
Page 23 of 104
 people with genotype 3 treatment-naive HCV, for whom interferon is
unsuitable, compared with no treatment
therapy is suitable, compared with peginterferon alfa and ribavirin.
3.46
The company also carried out probabilistic sensitivity analyses to explore
parameter uncertainty. Although it did not draw any specific conclusions
from the analyses, results suggested that sofosbuvir had less than a 50%
probability of being cost effective in 6 of the base-case comparisons (if the
maximum acceptable ICER was £20,000 per QALY gained) and greater
than a 50% probability of being cost effective in 9 of the base-case
comparisons (if the maximum acceptable ICER was £30,000 per QALY
gained).
3.47
During clarification, the company explored the effect of including a
transition probability from Cardoso et al. (2010) (0.005; 95% CI 0.013 to
0.002) from the sustained virological response cirrhotic health state to the
hepatocellular carcinoma health state in the economic model, and varied
the probability in line with the upper and lower limits of the 95%
confidence interval (see section 3.52). The ICERs from the company’s
exploratory analyses were slightly higher than those estimated in the
company’s base case (ranging from £7507 per QALY gained [for
sofosbuvir plus peginterferon alfa and ribavirin compared with boceprevir
plus peginterferon alfa and ribavirin in people who are eligible for
interferon, with genotype 1 treatment-naive HCV] to £54,957 per QALY
gained [for sofosbuvir plus ribavirin compared with 24 weeks of
peginterferon alfa-2a and ribavirin treatment in people with genotype 2
treatment-naive HCV, for whom interferon therapy is suitable]).
HCV and HIV co-infected populations
3.48
The company provided a separate economic analysis for people coinfected with HIV and HCV. In people with HIV and genotype 1 treatmentnaive HCV for whom interferon therapy is suitable, the company’s basecase ICER for sofosbuvir plus ribavirin treatment for 24 weeks compared
Page 24 of 104
with no treatment was £28,504 per QALY gained, or £43,836 per QALY
gained compared with peginterferon alfa-2a and ribavirin treatment for
48 weeks. The company’s base-case ICER for sofosbuvir plus ribavirin for
12 weeks compared with peginterferon alfa 2a and ribavirin treatment for
48 weeks in people with genotype 2 treatment-naive HCV and HIV-coinfection was £55,867 per QALY gained. The company’s base-case ICER
for sofosbuvir plus ribavirin for 24 weeks compared with no treatment in
people with genotype 2 treatment-experienced HCV and HIV co-infection
was £10,572 per QALY gained, or £128,248 per QALY gained compared
with peginterferon alfa-2a and ribavirin treatment for 48 weeks. For people
with genotype 3 treatment-naive HCV and HIV co-infection, 12 weeks of
sofosbuvir plus ribavirin dominated treatment with peginterferon alfa and
ribavirin. The ICERs for 24 weeks of sofosbuvir plus ribavirin were
£10,646 per QALY gained compared with no treatment and £90,822 per
QALY gained compared with peginterferon alfa-2a and ribavirin for
48 weeks in people with genotype 3 treatment-experienced HCV and HIV
co-infection. The company did not provide an economic analysis for
people co-infected with HIV and genotype 4, 5, or 6 HCV.
Evidence Review Group comments
3.49
The ERG reviewed the company’s model and economic systematic
review. The ERG considered that the company’s methods of economic
evaluation and the model produced were acceptable. It validated the
company’s model by comparing the total costs and QALYs predicted by
the model for the treatment-naive interferon-eligible genotype 1 HCV
population with the corresponding figures for treatment with peginterferon
alfa plus ribavirin with and without boceprevir or telaprevir obtained from
the previous NICE technology appraisals for boceprevir for the treatment
of genotype 1 chronic hepatitis C and telaprevir for the treatment of
genotype 1 chronic hepatitis C. The ERG found that the company’s model
for sofosbuvir was broadly consistent with previous models considered in
NICE technology appraisals for hepatitis C, in terms of total costs and
QALYs assumed for peginterferon alfa and ribavirin, and for telaprevir.
Page 25 of 104
However, the ERG noted that there was a discrepancy between models in
the total costs estimated for boceprevir, but it was not able to account for
the differences without reviewing the data used in the boceprevir
submission. The ERG also considered that the company’s economic
model captured most of the important aspects of the disease pathway, but
noted that it did not include a transition from the sustained virological
response cirrhotic health state to the hepatocellular carcinoma health
state, which had been previously included in other hepatitis C models.
Despite this omission from the company’s model, the ERG showed that it
did not affect the base-case ICERs substantially. The ERG considered
that the company’s model extrapolated intermediate outcomes to final
outcomes in a consistent way, drawing on standard sources from the
literature.
3.50
The ERG noted that the transition probabilities used by the company in its
economic model for the HCV and HIV co-infected population from the
non-cirrhotic to compensated cirrhosis health states were higher than
those assumed for the mono-infected population. The ERG further noted
that people with HCV and HIV co-infection are likely to have a higher
mortality than the population with HCV only, regardless of sustained
virological response, and this was not taken into account in the company’s
model. The ERG noted that a study by Van Der Helm et al. (2013)
concluded that the effects of HCV treatment on HIV progression needed
to be evaluated further. Therefore, in the ERG’s opinion, the evidence
needed to accurately evaluate the cost effectiveness of sofosbuvir in the
HCV and HIV co-infected population was not currently available.
Additional exploratory ERG analyses
3.51
The ERG carried out several exploratory analyses, which included:
 adding a transition probability from the sustained virological response
cirrhotic health state to the hepatocellular carcinoma health state and
exploring the effect of using different transition probabilities between
these 2 health states
Page 26 of 104
 assessing the effect on the ICERs of variations to all-cause mortality
probabilities
 evaluating the effect of changing the average age of entry into the
model
 using a range of alternative sustained virological response estimates
from studies of comparator treatments
 assessing the effect of an alternative distribution of people with
cirrhosis
 exploring the effect of the number of people having 24 weeks of
sofosbuvir compared with those having 12 weeks of sofosbuvir
 assessing the effect of using alternative utility increments after
sustained virological response.
3.52
The ERG heard from its clinical advisers that a transition from the
sustained virological response cirrhotic health state to the hepatocellular
carcinoma health state should be included in models for chronic
hepatitis C to reflect the clinical course of the disease. The ERG noted
that this transition was not included in the company’s economic model. In
addition, the ERG was unable to calculate the transition probability
between these 2 health states used by the company (0.005) in its
response to clarification based on the study by Cardoso et al. (see section
3.47). The ERG recalculated the transition probability using the Cardoso
et al. study, to produce a value of 0.0123 (95% CI 0.028 to 0.0218). The
effect of including this value (and also the upper and lower confidence
interval values) was explored by the ERG in a sensitivity analysis that
produced ICERs ranging from £7593 per QALY gained [for sofosbuvir
plus peginterferon alfa and ribavirin compared with boceprevir plus
peginterferon alfa and ribavirin in people with genotype 1 treatment-naive
HCV, for whom interferon therapy is suitable] to £60,887 per QALY gained
[for sofosbuvir plus ribavirin compared with 24 weeks of peginterferon alfa
and ribavirin treatment in people with genotype 2 treatment-naive HCV for
whom interferon therapy is suitable]).
Page 27 of 104
3.53
The ERG noted that the company used the simple average of mortality
from men and women to calculate the age-specific mortality used in the
model. The ERG commented that more men are treated for HCV in
clinical practice in England, therefore a weighted average should have
been used. During clarification, the company re-ran their economic model
with weighted average mortality probabilities, but did not indicate what
weights were used to obtain its results. The ERG carried out an
exploratory analysis using a weighting of 61% men and 39% women as
used in Wright et al. The ICERs from the ERG’s exploratory analyses
were slightly higher than those estimated in the company’s base case
(ranging from £7453 per QALY gained [for sofosbuvir compared with
boceprevir plus peginterferon alfa and ribavirin in people with genotype 1
treatment-naive HCV, for whom interferon therapy is suitable] to £50,083
per QALY gained [for sofosbuvir compared with no treatment in people
with genotype 1 treatment-naive HCV, for whom interferon is unsuitable]).
3.54
The ERG noted that the company’s model used an efficacy estimate
drawn from a single source when multiple efficacy estimates were
available for the same treatment and indication. NICE asked the ERG to
carry out further exploratory analyses to inform the Committee’s
understanding of the effect on the company’s ICERs of using a range of
alternative sustained virological response estimates from studies of
comparator treatments. For people with genotype 1 treatment-naive HCV,
the ERG used alternative estimates of sustained virological response for
boceprevir plus peginterferon alfa-2b and ribavirin from the SPRINT-2
study, in line with estimates used in the NICE technology appraisal of
boceprevir (that is, 68.2% for people with no cirrhosis and 41.7% for
people with cirrhosis, compared with the company’s base-case values of
64.1% for people with no cirrhosis and 55.0% for people with cirrhosis).
Applying the alternative sustained virological response estimates for
boceprevir gave a lower ICER than the company’s base case (the ICER
was not reported by the ERG in its additional analyses).
Page 28 of 104
3.55
The ERG also used alternative sustained virological response estimates
for people with genotype 3 treatment-naive HCV, who are eligible for
interferon. First, the ERG modelled the effect of an alternative sustained
virological response of 90.7% for sofosbuvir plus peginterferon alfa-2a
and ribavirin. This response was at the lower end of the 95% confidence
interval for the population with no cirrhosis from the sofosbuvir trials (an
estimate of 97.4% was used in the company’s base case, an average of
the sustained virological response from ELECTRON and PROTON). The
resulting ICER for sofosbuvir plus peginterferon alfa-2a and ribavirin
compared with peginterferon alfa-2a and ribavirin for this subgroup was
£23,772 per QALY gained (compared with the company’s base-case
ICER of £20,613 per QALY gained). The ERG also explored the effect of
an alternative sustained virological response of 92.3% for sofosbuvir plus
peginterferon alfa-2a and ribavirin in people with genotype 3 treatmentnaive HCV and cirrhosis. Applying this alternative response lowered the
ICER to £18,187 per QALY gained.
3.56
The ERG also explored the effect of alternative assumptions about the
natural history of chronic hepatitis C infection on the company’s ICERs. In
particular, it investigated the effect of assuming an alternative distribution
of cirrhosis. The ERG used a distribution for new and existing cirrhosis
obtained from Hartwell et al. (2011) based on data from a London
teaching hospital where 32% of existing patients with HCV and 10% of
new patients with HCV had cirrhosis. The results of the exploratory
analysis suggested that using this distribution increased the company’s
base-case ICERs for people with treatment-naive HCV and reduced the
ICERs for people with treatment-experienced HCV across all genotypes.
therapy was suitable, the ICER for sofosbuvir plus peginterferon alfa-2a
and ribavirin (12 weeks) compared with peginterferon alfa and ribavirin
(24 weeks) increased from £20,613 per QALY gained in the company’s
base case to £30,175 per QALY gained. The ICERs for treatment for
people with genotype 1 treatment-naive HCV remained above £30,000
Page 29 of 104
per QALY gained (irrespective of interferon eligibility). Results for all other
subgroups remained below £30,000 per QALY gained.
3.57
The ERG explored the effect of using a lower transition probability from
the non-cirrhotic health state to the compensated cirrhosis health state, at
age 40 years in the company’s model. The resulting ICERs increased
across all subgroups and were higher than those estimated in the
company’s base case (ranging from £9458 per QALY gained [for
sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin
in people with genotype 1 treatment-naive HCV, for whom interferon
therapy is suitable] to £61,077 per QALY gained [for sofosbuvir compared
with no treatment in people with genotype 1 treatment-naive HCV, for
whom interferon treatment is unsuitable]).
3.58
The ERG explored the effect on the company’s base-case ICERs of
varying the percentage of people having 24 weeks of sofosbuvir treatment
compared with those having 12 weeks of treatment. The 3 subgroups who
might have 12 or 24 weeks of sofosbuvir treatment according to the
marketing authorisation are people with:
 genotype 1 HCV, having sofosbuvir plus peginterferon alfa and ribavirin
 genotype 2 HCV, having sofosbuvir and ribavirin
 genotype 3 HCV, having sofosbuvir plus peginterferon alfa and
ribavirin.
The ERG’s clinical advisers differed in their opinions about how long these
groups would have treatment. One clinical expert stated that it would be
unlikely that more than 1-2% of people would be considered better off with
longer therapy and that this group are identified in the summary of product
characteristics as needing consideration for longer treatment periods.
Another clinical expert stated that at least 20% of people might need
24 weeks of therapy, especially those who are intolerant to interferon or
have severe cirrhosis.
Page 30 of 104
3.59
The ERG pointed out that the company’s economic model allows for a
12 week regimen of sofosbuvir plus peginterferon alfa and ribavirin for
is suitable and a 12 week regimen of sofosbuvir and ribavirin for people
with genotype 2 treatment-naive HCV (regardless of interferon eligibility).
The economic model did allow for a 24 week regimen of sofosbuvir and
ribavirin for various genotype 3 HCV subgroups. The ERG therefore
compared sofosbuvir plus ribavirin for 24 weeks with either peginterferon
alfa and ribavirin treatment for 24 weeks in people with genotype 3
treatment-naive HCV and either no treatment or 48 weeks of
peginterferon alfa and ribavirin treatment for people with genotype 3
treatment-experienced HCV. The resulting ICERs were more than double
the company’s base-case results (which assumed that these patient
groups only have 12 weeks of sofosbuvir and ribavirin).
3.60
The ERG carried out sensitivity analyses to evaluate the effect of
changing the average age of entry into the model. The resulting ICERs
generally decreased when a lower average age of 35 years was selected
for entry into the model, and were higher when the average age selected
was 55 years. The lowest ICERs ranged from £6717 per QALY gained
(using 35 years) to £9170 per QALY gained (using 55 years) for
sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin
in people with genotype 1 treatment-naive HCV, for whom interferon
therapy is suitable. The highest ICERs ranged from £47,254 per QALY
gained (using 35 years) to £60,976 per QALY gained (using 55 years) for
sofosbuvir compared with 24 weeks of peginterferon alfa-2a and ribavirin
treatment in people with genotype 2 treatment-naive HCV, for whom
interferon therapy is suitable.
3.61
The ERG also carried out sensitivity analyses to explore the effect on the
company’s ICERs of using different utility increments (0 and 0.04 [taken
from Vera-Llonch et al. 2013], compared with the company’s estimate of
0.05) after sustained virological response. The resulting ICERs in the
ERG’s sensitivity analysis were consistently higher than the company’s
Page 31 of 104
base-case results. When using a utility increment of 0.04, the ICERs
ranged from £7899 per QALY gained for sofosbuvir plus peginterferon alfa
and ribavirin compared with boceprevir plus peginterferon alfa and
ribavirin in people with genotype 1 treatment-naive HCV, for whom
interferon therapy is suitable, to £53,793 per QALY gained for sofosbuvir
plus peginterferon alfa and ribavirin compared with no treatment in people
with genotype 1 treatment-naive HCV, for whom interferon treatment is
unsuitable. When using a utility increment of 0, the ICERs ranged from
£12,732 per QALY gained for sofosbuvir plus peginterferon alfa and
ribavirin compared with boceprevir plus peginterferon alfa and ribavirin in
people with genotype 1 treatment-naive HCV, for whom interferon therapy
is suitable, to £92,795 per QALY gained for sofosbuvir plus peginterferon
alfa and ribavirin compared with no treatment in people with genotype 1
treatment-naive HCV, for whom interferon treatment is unsuitable.
3.62
The ERG also explored the effect on the company’s base-case ICERs
when alternative estimates of sustained virological response for
peginterferon alfa plus ribavirin to those used by the company (from
McHutchison et al. 2009) were applied, for people with genotype 1
treatment-naive HCV for whom interferon therapy is suitable. The ERG
used estimates from Roberts et al. (2009), which reported a sustained
virological response of 51% for people without cirrhosis and 6% for people
with cirrhosis, and estimates from Hadziyannis et al. (2004), which were
56% and 38% respectively. Using the estimates from Roberts et al. the
company’s ICER for sofosbuvir plus peginterferon alfa and ribavirin
compared with peginterferon alfa and ribavirin increased to £18,209 per
QALY gained. Similarly, the base-case ICER increased to £21,848 per
QALY gained for the same comparison when estimates from Hadziyannis
et al. were used.
3.63
The ERG also carried out a scenario analysis that considered the
combined impact on the company’s ICERs of including a transition from
the sustained virological response cirrhotic health state to the
hepatocellular carcinoma health state, alternative utility increments after a
Page 32 of 104
sustained virological response, and an alternative estimate of efficacy for
peginterferon alfa and ribavirin in the population with genotype 1
treatment-naive HCV who are eligible for interferon (using values
described in sections 3.52, 3.61 and 3.62). The ICERs from the ERG’s
exploratory analyses were higher than those estimated in the company’s
base case (ranging from £9415 per QALY gained [for sofosbuvir plus
peginterferon alfa and ribavirin compared with boceprevir plus
peginterferon alfa and ribavirin in people with genotype 1 treatment-naive
HCV, for whom interferon therapy is suitable] to £109,526 per QALY
gained [for sofosbuvir plus ribavirin compared with no treatment in people
with genotype 1 treatment-naive HCV, for whom interferon is unsuitable]).
Additional analyses for genotypes 1 and 3 HCV
3.64
During consultation the Committee asked that the company provide
additional evidence, which the Committee believed would permit it to
come to a better informed conclusion. Specifically, the Committee
requested that the company carry out several exploratory analyses for
sofosbuvir plus ribavirin, with or without peginterferon alfa, compared with
peginterferon alfa and ribavirin in people with genotype 1 and genotype 3
chronic hepatitis C, because these genotypes represent 89% of HCV
infections in England. This included revised cost-effectiveness analyses
presented separately for people with and without cirrhosis, with and
without HIV-co-infection, and by treatment history. The Committee asked
that the analyses should incorporate:
 the transition from the sustained virological response cirrhotic health
state to the hepatocellular carcinoma health state, using the transition
probability estimates from Cardoso et al.
 alternative sustained virological response estimates for peginterferon
alfa and ribavirin (for example from Hadziyannis et al.)
 alternative utility increments after sustained virological response (for
example SF-36 values from the trials collected at 24 weeks posttreatment, and Vera-Llonch et al.) and
Page 33 of 104
 alternative costs for ribavirin (for example, the cost of generic ribavirin
as calculated by the Commercial Medicines Unit Electronic Market
Information Tool) in the model.
The Committee also asked that sensitivity analyses, including the
Committee’s assumptions, should be explored:
 assuming that up to 100% of people with genotype 3 HCV have
sofosbuvir plus ribavirin for 24 weeks
 assuming that an increased proportion of people for whom interferon
therapy is suitable may be unwilling to have interferon treatment and
therefore have sofosbuvir plus ribavirin for 24 weeks
 varying the age of entry into the model from 35 and 55 years
 varying all-cause mortality by assuming the population entering the
model comprises 61% men and 39% women, in line with estimates
from Wright et al.
3.65
The company provided the additional analyses requested, although the
revised base-case assumptions were slightly different to those requested
by the Committee. The company justified each change to the revised
base-case assumptions, which included a transition from the sustained
virological response cirrhotic health state and the non-sustained
virological response cirrhotic health state to the hepatocellular carcinoma
health state, using the transition probability estimates from Cardoso et al.
(2010); alternative utility increments from Vera-Llonch et al., alternative
costs for ribavirin and all-cause mortality assuming the population entering
the model comprises 61% men and 39% women, in line with estimates
from Wright et al. The company chose to use the sustained virological
response rates for peginterferon alfa and ribavirin from McHutchison et al.
for its revised base case, and provided a sensitivity analysis incorporating
the sustained virological response rates from Hadziyannis et al. (see
section 3.74).
Page 34 of 104
3.66
The company presented ICERs to the Committee for subgroups stratified
by genotype, treatment history, interferon eligibility and cirrhosis status.
The company provided the Committee with a ‘global’ ICER based on all
patients mono-infected with HCV for genotypes 1 to 6, which was £16,199
per QALY gained. The company also provided the Committee with ‘global’
ICERs by genotype, weighted by treatment history and cirrhosis status,
which ranged from £10,753 per QALY gained in people with genotype 1
HCV to £31,361 per QALY gained in people with genotype 2 HCV.
Genotype 1
3.67
For people with treatment-naive genotype 1HCV, for whom interferon
therapy is suitable, the company’s revised base-case analysis showed
that the ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment
for 12 weeks compared with peginterferon alfa and ribavirin treatment for
48 weeks was £17,476 per QALY gained. The ICER for sofosbuvir plus
boceprevir plus peginterferon alfa and ribavirin was £10,335 per QALY
gained and £15,396 per QALY gained compared with telaprevir plus
peginterferon alfa and ribavirin. For people with genotype 1 treatmentnaive HCV, for whom interferon therapy is not suitable, the company’s
base-case ICER for sofosbuvir plus ribavirin for 24 weeks compared with
no treatment was £47,611 per QALY gained.
3.68
When stratified by the presence or absence of cirrhosis, the company’s
revised base-case analysis showed that the ICER for sofosbuvir plus
peginterferon alfa and ribavirin for 12 weeks compared with peginterferon
alfa and ribavirin treatment for 48 weeks in people with treatment-naive
HCV who are eligible for interferon was £25,237 per QALY gained for
people without cirrhosis, and £5352 for people with cirrhosis. The stratified
ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for
12 weeks compared with boceprevir plus peginterferon alfa and ribavirin
was £14,280 per QALY gained for people without cirrhosis and £2819 per
QALY gained for people with cirrhosis. The stratified ICER for sofosbuvir
Page 35 of 104
plus peginterferon alfa and ribavirin treatment for 12 weeks compared with
telaprevir plus peginterferon alfa and ribavirin was £22,304 per QALY
gained for people without cirrhosis and £4253 per QALY gained for people
with cirrhosis. For people with genotype 1 treatment-naive HCV for whom
interferon therapy is not suitable, the company’s base-case ICER for
sofosbuvir plus ribavirin for 24 weeks compared with no treatment,
stratified by cirrhosis status, was £51,478 per QALY gained for people
without cirrhosis and £35,754 per QALY gained for people with cirrhosis.
3.69
Because of the lack of clinical trial evidence in people with genotype 1
treatment-experienced HCV, the company provided the Committee with
an estimated cost-effectiveness calculation for this subgroup. The
company explained that historically, approximately 50% of people with
genotype 1 treatment-naive HCV had disease that responded to treatment
with peginterferon alfa and ribavirin, but in the interim analysis provided to
the US Food and Drug Administration (FDA), 89% of people with
genotype 1 treatment-naive HCV in NEUTRINO had disease that
responded to sofosbuvir plus peginterferon alfa and ribavirin. The FDA
accepted that the higher rate of overall sustained virological response
seen in NEUTRINO was likely driven by those patients who were virusfree 12 weeks after the end of treatment, but who would not have had this
response if treated with peginterferon alfa and ribavirin alone. Assuming
that people who would have had a sustained virological response with
peginterferon alfa and ribavirin alone had a sustained virological response
with sofosbuvir plus peginterferon alfa and ribavirin, the FDA assumed
that the increase in sustained virological response from 50% to 89%
represented the efficacy of sofosbuvir plus peginterferon alfa and ribavirin.
The FDA calculated that given the high sustained virological responses in
NEUTRINO, an approximate sustained virological response was 78% for
people with treatment-experienced genotype 1 HCV. Additionally, the
company presented interim evidence from Pol et al. (2013), a study of the
efficacy of sofosbuvir in people with genotype 1 treatment-experienced
HCV, which suggested that sustained virological responses in this group
Page 36 of 104
were 74% after treatment with sofosbuvir plus peginterferon alfa and
ribavirin for 12 weeks. Using the estimated sustained virological response
of 78% calculated by the FDA, the company’s ICER for sofosbuvir plus
alfa and ribavirin alone for 48 weeks was £12,641 per QALY gained. The
company’s ICER for sofosbuvir plus peginterferon alfa and ribavirin
treatment for 12 weeks compared with boceprevir plus peginterferon alfa
and ribavirin was £683 per QALY gained and £8203 per QALY gained
when compared with telaprevir plus peginterferon alfa and ribavirin in
people with genotype 1 treatment-experienced HCV.
Genotype 3
3.70
therapy is suitable, the company’s revised base-case ICER for sofosbuvir
plus peginterferon alfa and ribavirin treatment for 12 weeks compared with
QALY gained. In people with genotype 3 treatment-naive HCV for whom
interferon therapy is unsuitable, the company’s base-case ICER for
sofosbuvir plus ribavirin for 24 weeks compared with no treatment was
£21,049 per QALY gained.
3.71
interferon therapy is suitable, the company’s base-case ICER for
£13,883 per QALY gained. In people with genotype 3 treatmentexperienced HCV, for whom interferon therapy is unsuitable, the
company’s base-case ICER for sofosbuvir plus ribavirin for 24 weeks
compared with no treatment was £27,483 per QALY gained.
3.72
When stratified by the absence or presence of cirrhosis, in people with
genotype 3 treatment-naive HCV for whom interferon therapy is suitable,
the company’s revised base-case ICER for sofosbuvir plus peginterferon
alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa
Page 37 of 104
and ribavirin treatment for 24 weeks was £40,623 per QALY gained for
people without cirrhosis and £6556 per QALY gained for people with
cirrhosis. In people with genotype 3 treatment-naive HCV for whom
interferon therapy is unsuitable, the company’s revised base-case ICER
for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was
£28,044 per QALY gained in people with no cirrhosis, and £10,505 per
QALY gained in people with cirrhosis. In people with treatmentexperienced genotype 3 HCV for whom interferon therapy is suitable, the
company’s revised base-case ICER for sofosbuvir plus peginterferon alfa
and ribavirin treatment for 12 weeks compared with peginterferon alfa and
ribavirin treatment for 48 weeks was £18,592 per QALY gained in people
without cirrhosis and £6260 per QALY gained in people with cirrhosis. In
people with genotype 3 treatment-experienced HCV for whom interferon
therapy is unsuitable, the company’s revised base-case ICER for
£31,416 per QALY gained in people without cirrhosis and £19,179 per
QALY gained in people with cirrhosis.
HCV and HIV co-infected populations
3.73
The company provided a separate economic analysis for people coinfected with HIV and HCV. The company reported results from the 1910
study (Rodriguez-Torres et al. [2013]), which included (F0-F3) patients
with HCV and HIV co-infection and no cirrhosis. The sustained virological
response of 90% seen in the 1910 study was also seen in people with
HCV mono-infection and no cirrhosis in NEUTRINO, which suggested that
similar response rates are seen in people with genotype 1 HCV having
sofosbuvir plus peginterferon and ribavirin for 12 weeks, regardless of
HCV and HIV co-infection status. The company presented revised basecase ICERs in people co-infected with HIV and genotype 1 or 3 HCV,
which ranged from £10,376 per QALY gained in people with genotype 3
treatment-experienced HCV and HIV having sofosbuvir and ribavirin for
24 weeks compared with no treatment, to £27,059 per QALY gained in
Page 38 of 104
people with genotype 1 treatment-naive HCV having sofosbuvir and
ribavirin for 24 weeks compared with no treatment.
Additional sensitivity analyses
3.74
The Committee asked that the revised base case include the sustained
virological responses from Hadziyannis et al. rather than from
McHutchison et al. for peginterferon alfa and ribavirin in people with
genotype 1 treatment-naive HCV. The company expressed concern about
this approach because the sustained virological response in Hadziyannis
et al. assumed that a METAVIR score from F0 to F2 represented people
without cirrhosis and a score from F3 to F4 represented people with
cirrhosis, whereas in NEUTRINO, METAVIR scores of F4 for cirrhosis and
F0-F3 for non-cirrhosis were defined. The company also commented that
people in the McHutchison et al. study were more representative of
people in the NEUTRINO study. Therefore, the company used the
sustained virological responses from McHutchison et al. in its revised
base-case analysis. However, it provided the Committee with the results
of a scenario analysis in which it used the sustained virological responses
for peginterferon alfa and ribavirin from Hadziyannis et al., which
suggested that for people with genotype 1 treatment-naive HCV, the ICER
for sofosbuvir plus peginterferon alfa and ribavirin compared with
peginterferon alfa and ribavirin alone was £25,014 per QALY gained,
whereas its revised base-case ICER using the sustained virological
responses for peginterferon alfa and ribavirin from McHutchison et al. was
3.75
The company presented a scenario analysis assuming that 100% of
people with genotype 3 HCV for whom interferon therapy is suitable would
have 24 weeks of sofosbuvir and ribavirin. In people with genotype 3
treatment-naive HCV for whom interferon therapy is suitable, assuming
that 100% of people would have 24 weeks of sofosbuvir and ribavirin
treatment compared with 24 weeks of peginterferon alfa and ribavirin
treatment, the ICER was £46,956 per QALY gained. In people with
Page 39 of 104
genotype 3 treatment-experienced HCV for whom interferon therapy is
suitable, assuming that 100% of people would have 24 weeks of
sofosbuvir and ribavirin treatment compared with 48 weeks of
peginterferon alfa and ribavirin treatment, the ICER was £48,306 per
QALY gained. The company also presented the results of a scenario
analysis using the upper (20%) and lower (2%) proportion of people with
genotype 3 HCV for whom interferon therapy is suitable and who were
expected to have sofosbuvir and ribavirin for 24 weeks as suggested by
the ERG’s clinical advisers. In people with genotype 3 treatment-naive
HCV for whom interferon therapy is suitable, assuming that 2% of people
would have 24 weeks of sofosbuvir and ribavirin treatment compared with
24 weeks of peginterferon alfa and ribavirin treatment, the ICER was
£22,385 per QALY gained, and £27,062 per QALY gained when 20% was
used. In people with genotype 3 treatment-experienced HCV for whom
interferon therapy is suitable, assuming that 2% of people would have
24 weeks of sofosbuvir and ribavirin treatment compared with 24 weeks of
peginterferon alfa and ribavirin treatment, the ICER was £14,467 per
QALY gained and £19,890 per QALY gained when 20% was used.
3.76
The ERG reviewed the company’s additional evidence. The ERG noted
that the company had used most of the Committee’s preferred base-case
assumptions (see section 3.64). It further noted that the company did not
provide a sensitivity analysis exploring the impact on the ICER of using
utility data collected in the clinical trials. The ERG carried out an
exploratory analysis in which it used all of the Committee’s preferred
assumptions to calculate the ICERs for treatment for people with
genotype 1 and 3 HCV and also carried out the exploratory scenario
analyses requested by the Committee (see section 3.64). The ERG’s
exploratory analyses resulted in an ICER for sofosbuvir plus peginterferon
alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa
and ribavirin treatment for 48 weeks of £30,993 per QALY gained for
people with treatment-naive genotype 1 HCV, for whom interferon therapy
is suitable. The ICER for sofosbuvir plus peginterferon alfa and ribavirin
Page 40 of 104
treatment for 12 weeks compared with boceprevir plus peginterferon alfa
and ribavirin was £12,172 per QALY gained and £18,704 per QALY
gained compared with telaprevir plus peginterferon alfa and ribavirin. For
people with genotype 1 treatment-naive HCV, for whom interferon therapy
is unsuitable, the base-case ICER for sofosbuvir plus ribavirin for
24 weeks compared with no treatment was £58,113 per QALY gained.
3.77
The ERG stratified the exploratory ICERs by the presence or absence of
cirrhosis. The ICER for sofosbuvir plus peginterferon alfa and ribavirin for
12 weeks compared with peginterferon alfa and ribavirin treatment for
48 weeks was £38,460 per QALY gained for people without cirrhosis, and
£12,891 for people with cirrhosis. The ICER for sofosbuvir plus
boceprevir plus peginterferon alfa and ribavirin was £15,653 per QALY
gained for people without cirrhosis and £2274 per QALY gained for people
with cirrhosis. The ICER for sofosbuvir plus peginterferon alfa and
ribavirin treatment for 12 weeks compared with telaprevir plus
peginterferon alfa and ribavirin was £24,509 per QALY gained for people
without cirrhosis and £4680 per QALY gained for people with cirrhosis
compared with telaprevir plus peginterferon alfa and ribavirin. For people
with genotype 1 treatment-naive HCV for whom interferon therapy is
unsuitable, the base-case ICER for sofosbuvir plus ribavirin for 24 weeks
compared with no treatment was £58,118 per QALY gained for people
without cirrhosis and £58,093 per QALY gained for people with cirrhosis.
3.78
In people for whom interferon therapy is suitable, with genotype 3
treatment-naive HCV, the ERG’s exploratory analyses resulted in an ICER
for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks
compared with peginterferon alfa and ribavirin treatment for 24 weeks of
£28,666 per QALY gained. In people with genotype 3 treatment-naive
HCV for whom interferon therapy is unsuitable, the base-case ICER for
£26,611 per QALY gained. In people with genotype 3 treatmentexperienced HCV for whom interferon therapy is suitable, the ERG’s
Page 41 of 104
exploratory analyses showed that the ICER for sofosbuvir plus
QALY gained. In people with genotype 3 treatment-experienced HCV, for
whom interferon therapy is unsuitable, the company’s base-case ICER for
3.79
When stratified by the presence or absence of cirrhosis, in people with
genotype 3 treatment-naive HCV for whom interferon therapy is suitable,
the ERG’s exploratory analyses resulted in an ICER for sofosbuvir plus
peginterferon alfa and ribavirin treatment for 24 weeks that was £46,036
per QALY gained for people without cirrhosis and £8318 per QALY gained
for people with cirrhosis. In people with genotype 3 treatment-naive HCV
for whom interferon therapy is suitable, the ERG’s exploratory analyses
showed that the ICER for sofosbuvir plus ribavirin for 24 weeks compared
with no treatment was £31,851 per QALY gained in people with no
cirrhosis, and £15,133 per QALY gained in people with cirrhosis. In people
with treatment-experienced genotype 3 HCV for whom interferon therapy
is suitable, the ERG’s exploratory analyses showed that the ICER for
£20,694 per QALY gained in people without cirrhosis and £8093 per
QALY gained in people with cirrhosis. In people with genotype 3
treatment-experienced HCV for whom interferon therapy is unsuitable, the
ERG’s exploratory analyses showed that the ICER for sofosbuvir plus
gained in people without cirrhosis and £29,704 per QALY gained in
people with cirrhosis.
Page 42 of 104
Additional analyses in genotype 4, 5 and 6 HCV
3.80
During consultation several consultees, including the company, asked that
the Committee reconsider the clinical and cost-effectiveness evidence for
people with genotype 4 HCV. The consultees indicated that people with
genotype 4 HCV represent a group with a particularly high unmet need
and minority ethnic groups represent a higher proportion of people who
have genotype 4 HCV in the UK. Whereas genotype 4 HCV accounts for
5% of all HCV genotypes in the UK (but is more prevalent in the Middle
East and Africa), the prevalence of genotype 4 in the UK is increasing
because of migration, HIV co-infection and intravenous drug use.
Additionally, a consultee stated that the proportion of people with
genotype 4 HCV who have haemophilia is higher than in other genotypes
because of infection with blood products imported from abroad.
3.81
In order to fully explore the potential equality issues raised during
consultation, additional evidence was requested from the company, which
included HCV prevalence data by genotype and family origin, HIV coinfection and haemophilia in the UK. The company provided NICE with
evidence from a HCV genotype surveillance report commissioned by the
company to be produced by Public Health England, which showed the
proportion of people with genotype 1 or 3 HCV who were of white or white
British family origin was 81% and 72% respectively, whereas minority
ethnic groups represented 8% and 18% respectively. The proportion of
people with genotypes 4, 5 and 6 HCV who were of white or white British
family origin was 44%, 53% and 19%, respectively, whereas minority
ethnic groups represented 39%, 28% and 74%, respectively (see table 5).
Table 5 Genotype by family origin
HCV
genotype
1
2
3
4
White or
white British
(%)
13675 (81)
1883 (84)
12001 (72)
593 (44)
Asian or Asian
British (%)
Black or black
British (%)
Other or mixed
origin (%)
Unknown
(%)
875 (5)
75 (3)
2894 (17)
378 (28)
116 (1)
12 (1)
37 (0.22)
48 (4)
265(2)
35 (2)
146 (0.88)
90 (7)
2023 (12)
239 (11)
1532 (9)
239 (18)
Page 43 of 104
5
25 (53)
6
12 (19)
Non-1
46 (70)
Dual
13 (59)
HCV; hepatitis C virus
3.82
7 (15)
4 (6)
3 (5)
6 (27)
6 (13)
1 (2)
0 (0)
0 (0)
0 (0)
42 (66)
1 (2)
0 (0)
9 (19)
5 (8)
16 (24)
3 (14)
The company also provided genotype distribution data from the 2012
United Kingdom Haemophilia Centre Doctors' Organisation look-back
exercise, which reported a prevalence of 3% and 1% of HCV genotypes 4
and 5 respectively among UK HCV-infected people with haemophilia. The
proportion of people with haemophilia with genotypes 1, 2 and 3 HCV is
96%. Additionally, the company presented commercial-in-confidence
evidence that a disproportionate number of people with HIV co-infection
have genotype 4 HCV compared with people without HIV co-infection.
3.83
The Committee requested that the company submit a literature review of a
range of sustained virological responses for peginterferon alfa and
ribavirin to address uncertainty in the sustained virological responses in
the comparator arm of the economic model. The company identified
7 studies reporting efficacy data for patients with genotype 4, 5 or 6 HCV
in its systematic literature review. The company excluded all studies that
recruited solely from Egypt, Africa, Asia or the Middle East because of
documented differences in baseline characteristics and response to
treatment. According to the company, only Manns et al. (2001) and
Lindsay et al. (2001) provided combined data on genotypes 4, 5 and 6
HCV. Of these studies, Manns et al. included more patients (n=16)
compared with Lindsay et al. (n=8). The company supported the use of
Manns et al. with unpublished data from Imperial College London, which
provides treatment for the largest numbers of people with genotype 4
HCV in England, suggesting that the sustained virological response of
50% from Manns et al. in people without cirrhosis was similar to the rate
observed at Imperial College (49.5% in patients with genotype 4 having
peginterferon alfa and ribavirin for 48 weeks). The company also
calculated the sustained virological response for people with genotype 4,
Page 44 of 104
5 or 6 HCV with cirrhosis to be 38.6% based on the relative difference in
sustained virological response between people without cirrhosis and
people with cirrhosis in the studies in genotype 1, 2 and 3 HCV.
3.84
The ERG did not agree that only studies that included combined
genotypes 4, 5 and 6 HCV should be analysed, because this approach
excluded some trials of genotype 4 HCV that have larger sample sizes.
The ERG did its own rapid systematic literature review that identified
17 studies with sample sizes of 10 or more people with genotype 4 HCV.
Ten of the studies took place in the Middle East (particularly Egypt) and 7
were from Europe (3 were randomised controlled studies, 4 were nonrandomised studies). The ERG calculated the overall weighted mean
sustained virological response for the 4 well-reported Middle Eastern
studies out of the 10 and the 3 randomised controlled studies from the 7
European studies separately, resulting in a sustained virological response
of 65.6% and 55.7%, respectively. When all 17 studies were combined
with Manns et al. and Lindsay et al., the resulting weighted sustained
virological response was 54.8%. The ERG’s clinical advisers provided
comment on the relevance of the Middle Eastern studies to NHS practice,
stating that there is a significant difference between patients of Egyptian
family origin in Europe and those in Egypt, because the average age and
number of comorbidities is higher in most European studies, which
translates into a reduced response rate.
3.85
The Committee also asked the company to provide a revised base-case
ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for
12 weeks compared with peginterferon alfa and ribavirin treatment for
48 weeks for people with genotype 4, 5 or 6 treatment-naive HCV, using
the Committee’s preferred assumptions, which were using:
 the Cardoso et al. transition probabilities from the sustained virological
response with cirrhosis health state and the cirrhosis health state
without a sustained virological response to the hepatocellular
carcinoma health state
Page 45 of 104
 the utility increment after a sustained virological response from VeraLlonch et al. and
 a men:women distribution ratio from Wright et al.
The Committee also requested that the company show the impact of
alternative sustained virological responses for peginterferon alfa and
ribavirin alone for 48 weeks from the systematic review of published
sources included in its initial submission to the Committee, together with a
rationale for the preference of Manns et al. in the revised base-case
model over other sources.
3.86
The company used the sustained virological responses observed in
NEUTRINO for the sofosbuvir plus peginterferon alfa and ribavirin arm of
the model. The revised base-case ICER for sofosbuvir plus peginterferon
alfa and ribavirin for 12 weeks compared with peginterferon alfa and
ribavirin for 48 weeks (using the sustained virological response of 50% for
peginterferon alfa and ribavirin from Manns et al.) increased from £26,797
per QALY gained in the original model to £27,505 per QALY gained in the
revised base-case model. The company had identified 7 studies, which
included peginterferon alfa and ribavirin for 48 weeks in a treatment arm
with sustained virological responses ranging from 33% (Zeuzem et al.
2005) to 77% (Fried et al. 2002). These sustained virological responses
were not stratified by cirrhosis status, therefore the company applied the
same sustained virological response for people without cirrhosis as for
people with cirrhosis in the model. Sustained virological responses for
sofosbuvir plus peginterferon alfa and ribavirin from the NEUTRINO study
were stratified by cirrhosis status (100% for people without cirrhosis and
50% for people with cirrhosis). The resulting ICERs for sofosbuvir plus
alfa and ribavirin for 48 weeks using the sustained virological response
from Zeuzem et al. (33%) was £19,148 per QALY gained, and £244,387
per QALY gained when Fried et al. (77%) was used. The company also
calculated the ICER for sofosbuvir plus peginterferon alfa and ribavirin for
Page 46 of 104
12 weeks compared with peginterferon alfa and ribavirin for 48 weeks
using the sustained virological response of 97% for the combined cohort
of people with and without cirrhosis in NEUTRINO. The resulting ICER
was £47,394 per QALY gained.
3.87
The company provided a sensitivity analysis that used the transition
probability from the compensated cirrhosis without a sustained virological
response health state to hepatocellular carcinoma from Fattovich et al.
(1997) rather than Cardoso et al., which increased the ICERs from
£27,505 to £31,713 per QALY gained in the revised base case. When the
sustained virological response for peginterferon alfa and ribavirin for 48
weeks from Zeuzem et al. and Fried et al. were used, the ICERs were
£22,096 and £151,837 per QALY gained, respectively.
3.88
The ERG used the same revised base-case assumptions as the company
and applied the weighted sustained virological response from the
17 studies it identified, which resulted in a ICER of £37,820 per QALY
gained and increased to £40,761 per QALY gained when the transition
probability from Fattovich et al. was used for the transition from
compensated cirrhosis without a sustained virological response to
hepatocellular carcinoma. When the ERG used the weighted sustained
virological response from the 10 Middle Eastern studies, the ICER for
sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared
with peginterferon alfa and ribavirin for 48 weeks was £69,181 per QALY
gained, whereas the ICER using the 7 European studies in people with
genotype 4 HCV only was £40,664 per QALY gained, and £39,109 per
QALY gained when the 7 European studies were supplemented with the
results from Manns et al. and Lindsay et al.
3.89
Full details of all the evidence are in the committee papers.
4
Consideration of the evidence
4.1
The Appraisal Committee reviewed the data available on the clinical and
cost effectiveness of sofosbuvir, having considered evidence on the
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nature of chronic hepatitis C and the value placed on the benefits of
sofosbuvir by people with the condition, those who represent them, and
clinical experts. It also took into account the effective use of NHS
resources.
4.2
The Committee heard from the clinical experts that chronic hepatitis C is
often clinically asymptomatic, and that it is estimated to be undiagnosed in
approximately 50% of people with the condition in England. However,
when the condition progresses and cirrhosis occurs, it has a significant
daily effect on the person with the virus and their carers. The Committee
acknowledged the concerns of the patient experts that there is a stigma
attached to having chronic hepatitis C, because of its link to injectable
drug use. In addition, there is a reluctance to treat chronic hepatitis C in
people who use injectable drugs, partly because of mistaken beliefs that
they do not adhere to treatment and often become re-infected. The
Committee heard from the patient experts that the availability of
sofosbuvir and other new treatments that are expected to become
available over the next 5 years will encourage more people with chronic
hepatitis C to seek diagnosis and treatment. In addition, people who use
injectable drugs whose chronic hepatitis C is successfully treated may go
on to address their drug use, leading to broader societal benefits that are
not captured in the company’s evidence submission. The Committee
recognised the effect of chronic hepatitis C on the lives of people with the
virus. It concluded that treatments that give a sustained virological
response (which is considered equivalent to a cure), and that
consequently help reduce the rate of HCV transmission and the stigma
associated with having chronic hepatitis C, are of significant importance.
4.3
The Committee discussed the clinical management of chronic hepatitis C
in adults. It heard from the clinical experts that different treatment options
can have varied results, depending on the person’s HCV genotype, level
of liver damage, comorbidities and previous treatment history. For people
with genotype 1 chronic hepatitis C, the Committee heard that boceprevir
plus peginterferon alfa and ribavirin or telaprevir plus peginterferon alfa
Page 48 of 104
and ribavirin (see the NICE technology appraisal guidance on boceprevir
for the treatment of genotype 1 chronic hepatitis C and telaprevir for the
treatment of genotype 1 chronic hepatitis C) are commonly used, and that
for people with genotypes 2 to 6 HCV, peginterferon alfa plus ribavirin or
watchful waiting (closely monitoring the condition but not giving any
treatment) are currently the main treatment options. The clinical experts
highlighted that interferon-based treatment can be associated with side
effects such as chronic fatigue, neuropsychological effects and flu-like
symptoms, which can be a barrier to people wanting to start treatment, or
taking their treatment for the recommended duration. The Committee also
heard from the patient experts that interferon-based treatment may cause
chronic side effects, such as autoimmune responses and thyroid
problems, which need additional long-term management and therefore
pose another barrier to people starting and completing treatment. The
Committee acknowledged that the marketing authorisation for sofosbuvir
offers people the option to have shortened courses of peginterferon alfa
and ribavirin, or in some circumstances to have treatment without
peginterferon alfa, thereby reducing potential adverse effects associated
with interferon-based therapy. The Committee agreed with the clinical
experts and patient experts that the option to have a shortened course of
interferon-based therapy with sofosbuvir, or the possibility of sofosbuvir
being used without peginterferon alfa in some circumstances, would make
it a valuable treatment option for people with chronic hepatitis C.
4.4
The Committee acknowledged that the marketing authorisation in the UK
for sofosbuvir licenses it to be used in adults with chronic hepatitis C in all
genotypes. It heard from the clinical experts that in England, most people
with chronic hepatitis C have genotypes 1 or 3 HCV (46% and 43%
respectively), with genotype 1 HCV being associated with a poor
response to antiviral therapy and an increased rate of progression to
severe chronic liver disease. The Committee noted that the marketing
authorisation also allows sofosbuvir to be used in people who have or
have not had previous treatment for chronic hepatitis C. The Committee
Page 49 of 104
also noted that the marketing authorisation allows sofosbuvir in
combination with ribavirin, to be used in people with genotypes 1, 4, 5, or
6 who could be considered interferon intolerant or ineligible and who are
in urgent need of treatment. It heard from company representatives that
people would be considered interferon intolerant or ineligible if interferon
treatment was contraindicated (as described in the summary of product
characteristics for peginterferon) or in people whose disease did not have
an adequate response to previous interferon treatment. The Committee
asked the clinicians and commissioners for a definition of who would be
considered interferon intolerant or ineligible, but did not receive a clear
response. The Committee heard from the clinical experts that sofosbuvir
is an important new treatment that will address an unmet need,
particularly in people who have previously been treated but did not have a
sustained virological response, in people whose condition has relapsed,
or in people who have become re-infected after treatment. The Committee
was aware that the marketing authorisation specifies that sofosbuvir
treatment should be ‘initiated and monitored by a physician experienced in
the management of patients with chronic hepatitis C’. It agreed with
comments received during consultation that treatment should be focused
in specialist centres and that treatment decisions, such as determining
whether someone is interferon intolerant or ineligible for interferon
treatment, should be made preferably by a multidisciplinary team. The
Committee concluded that most people with chronic hepatitis C are likely
to have at least some benefit from adding sofosbuvir to their treatment
regimen and that the condition should be treated in an appropriate setting,
as specified in the sofosbuvir marketing authorisation.
Clinical effectiveness
4.5
The Committee considered the clinical effectiveness of sofosbuvir plus
ribavirin, with or without peginterferon alfa, for people with genotypes 1 to
6 chronic hepatitis C. It noted the concerns of the Evidence Review Group
(ERG) that because of the lack of head-to-head studies comparing
sofosbuvir with current standard of care treatments, most of the evidence
Page 50 of 104
provided by the company did not directly address the decision problem.
The Committee acknowledged that the company was able to provide
evidence from only 1 head-to-head trial (FISSION, in people with
genotype 2 or 3 treatment-naive HCV, for whom interferon therapy is
suitable; see sections 3.8–3.9) that was consistent with the decision
problem. The Committee was aware that the direct comparison with
standard of care treatment was further limited to people with genotype 2
HCV only because the marketing authorisation recommends 24 weeks of
sofosbuvir and ribavirin treatment for people with genotype 3 HCV, but
people with genotype 3 HCV in the FISSION study had 12 weeks of
sofosbuvir and ribavirin. In addition, the Committee expressed concern
about the robustness of the estimates of the clinical effectiveness of
sofosbuvir across the different subgroups for whom it is licensed when
stratified (grouped) by treatment history, presence or absence of cirrhosis,
and interferon eligibility, given that most trials were single-arm and openlabel with historical controls that only included relatively small patient
numbers and provided short-term data. The Committee heard from the
clinical experts that the current standard of care has been used for many
years in the UK, and has been supported by numerous trials; therefore it
was not unreasonable to use historical controls. The clinical experts also
commented that hepatitis C trials are often open label because some
people realise they are taking an interferon-based regimen, potentially
making blinding difficult. The Committee was aware that the number of
people with cirrhosis in the clinical trials was relatively small, although it
reflected the proportion of people with cirrhosis seen in clinical practice,
and the exclusion criteria meant that people who use injectable drugs
were not included in any studies. The Committee acknowledged the
limitations of carrying out trials for hepatitis C, and concluded that there
was considerable uncertainty surrounding the evidence base presented
by the company. Therefore the true magnitude of the effect of sofosbuvir
in each subgroup could not be robustly estimated.
Page 51 of 104
4.6
The Committee acknowledged that in the NEUTRINO trial, people with
genotype 1 (89% of people in the trial), 4, 5 or 6 treatment-naive HCV who
had sofosbuvir plus peginterferon alfa and ribavirin had a high sustained
virological response (91%) 12 weeks after treatment compared with the
historical control of 60% that was presented by the company. The
Committee concluded that sofosbuvir plus peginterferon alfa and ribavirin
was clinically more effective than peginterferon alfa and ribavirin alone in
inducing a sustained virological response in people with treatment-naive
genotype 1, 4, 5 or 6 HCV.
4.7
The Committee considered the clinical effectiveness of sofosbuvir plus
peginterferon alfa and ribavirin in people with treatment-experienced
genotype 1, 4, 5 or 6 HCV. No trial data were available on the clinical
effectiveness of sofosbuvir in people with these genotypes who had
previously had treatment for HCV. The Committee heard from the clinical
experts that there was no reason to expect a different response in
treatment-experienced HCV than in treatment-naive HCV. The Committee
also heard from clinical experts that it was unlikely that further studies of
sofosbuvir plus peginterferon alfa and ribavirin in people with treatmentexperienced HCV would be started because new interferon-free regimens
are rapidly replacing older interferon-based regimens. The Committee
was aware of the evidence from the company that the US Food and Drug
Administration had accepted that the increase in sustained virological
response in people with genotype 1 treatment-naive HCV from 50% to
89% in NEUTRINO (subsequently recalculated as 91%) represented an
efficacy of 78% for sofosbuvir plus peginterferon alfa and ribavirin in those
people who would not have a sustained virological response with
peginterferon alfa and ribavirin alone (see section 3.69). The Committee
also considered interim results from an ongoing open-label, single-arm
study by Pol et al. (2013) on the efficacy of sofosbuvir plus peginterferon
alfa and ribavirin in people with genotype 1 treatment-experienced HCV,
which the company provided during consultation. These interim data
suggested that 74% of patients who did not previously have a sustained
Page 52 of 104
virological response with peginterferon alfa plus ribavirin plus another
direct-acting antiviral (ledipasvir or tegobuvir) had a sustained virological
response 12 weeks after treatment with sofosbuvir plus peginterferon alfa
and ribavirin. The Committee also considered that in the small numbers of
people with genotype 4, 5 or 6 HCV in the NEUTRINO study (in people
with treatment-naive genotype 1, 4, 5 and 6 HCV), the sustained
virological responses 12 weeks after sofosbuvir treatment were
approximately 97%, which was similar to those in people with genotype 1
HCV (see section 3.3). The Committee concluded that although there was
uncertainty about the robustness of the evidence base in people with HCV
genotype 1, 4, 5 or 6 who have had HCV treatment before, there was
sufficient evidence for the Committee to make a recommendation on the
use of sofosbuvir in people with genotype 1, 4, 5 or 6 treatmentexperienced HCV.
4.8
The Committee discussed the design of the clinical trials for sofosbuvir
plus ribavirin in people with genotype 2 and 3 HCV. It noted that the main
evidence came from 4 trials (FISSION, [treatment-naive HCV, interferoneligible], FUSION, [treatment-experienced HCV], POSITRON [treatmentnaive and treatment-experienced HCV, people who were ineligible for
interferon or intolerant to it or unwilling to have it] and VALENCE
[treatment-naive and treatment-experienced]. The Committee
acknowledged that FISSION was the only trial with an active comparator
(peginterferon alfa-2a and ribavirin treatment for 24 weeks) but noted that
it was an open-label study, which was susceptible to the introduction of
selection bias and that when broken down by genotype, treatment history,
interferon eligibility and cirrhosis status, the results were based on small
patient numbers. The Committee was also aware that sustained
virological response in the combined study population (FISSION) was
67% in both the sofosbuvir plus ribavirin 12 week treatment arm and in the
peginterferon alfa-2a and ribavirin 24 week treatment arm. The Committee
noted that when stratified by genotype, people with genotype 2 HCV had
a higher sustained virological response with 12 weeks of sofosbuvir plus
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ribavirin (97%) than people having peginterferon alfa and ribavirin alone
(78%). The Committee noted that people with genotype 3 HCV having
12 weeks of sofosbuvir plus ribavirin had a lower sustained virological
response rate 12 weeks after treatment (56%) than people receiving
peginterferon alfa and ribavirin alone for 24 weeks (63%). The Committee
was aware that all 4 trials in people with genotype 2 and 3 HCV had small
patient numbers in each stratified subgroup (by genotype, treatment
history, interferon eligibility and cirrhosis) and different designs, and
concluded that these factors introduced uncertainty around the clinical
effectiveness of sofosbuvir. On balance, the Committee concluded that
sofosbuvir plus ribavirin was clinically more effective than peginterferon
alfa and ribavirin alone in inducing a sustained virological response at
12 weeks after treatment in people with genotype 2 HCV.
4.9
The Committee further considered the results of the VALENCE study,
which showed that longer treatment with sofosbuvir plus ribavirin was
needed for people with genotype 3 treatment-naive HCV (24 weeks rather
than 12 weeks) to obtain a comparable sustained virological response at
12 weeks after treatment to that seen in people with genotype 2 HCV
(data not reported here; academic-in-confidence). This was also
supported by the results of FISSION, which showed that the sustained
virological response for 12 weeks treatment with sofosbuvir and ribavirin
in people with genotype 3 HCV was consistently lower than that seen in
people with genotype 3 HCV who had peginterferon alfa-2a and ribavirin
for 24 weeks (see section 3.9). The Committee also discussed the clinical
effectiveness of sofosbuvir in people with genotype 2 and 3 treatmentexperienced HCV, noting that the evidence for this subgroup came from
FUSION (which compared sofosbuvir plus ribavirin for 12 weeks [plus
placebo for an extra 4 weeks] with sofosbuvir and ribavirin for 16 weeks),
and from subpopulations in VALENCE. The Committee noted that
sustained virological response was consistently higher for people with
genotype 2 HCV (86% and 94% in the 12 week and 16 week treatment
groups in FUSION; 93% after 12 weeks treatment in VALENCE) than for
Page 54 of 104
people with genotype 3 HCV, who needed longer treatment with
sofosbuvir and ribavirin (16 weeks and 24 weeks) for a similar response to
be shown. The Committee noted that in the studies people with cirrhosis
also generally had a lower response than those without cirrhosis
(irrespective of genotype). The Committee considered that treatment with
sofosbuvir plus ribavirin was likely to lead to a better sustained virological
response in people with genotype 3 HCV compared with the current
standard of care (24 weeks of peginterferon alfa and ribavirin treatment),
but only when sofosbuvir plus ribavirin treatment was extended to
24 weeks. The Committee concluded that taking into account the
limitations of the trial designs and the use of historical controls there was
considerable uncertainty around the true magnitude of benefit of
sofosbuvir plus ribavirin compared with peginterferon alfa and ribavirin for
24 weeks in people with genotype 3 HCV.
4.10
The Committee considered the available evidence for sofosbuvir plus
peginterferon alfa and ribavirin in people with genotype 3 HCV. The
Committee was aware that the European public assessment report for
sofosbuvir stated that because peginterferon alfa and ribavirin alone had a
higher historical efficacy in people with genotype 3 HCV than in people
with genotype 1 HCV, it could be inferred that a similar improvement in
efficacy seen in people with genotype 1 HCV would be expected in people
with genotype 3 HCV when sofosbuvir was added to peginterferon alfa
and ribavirin. This was supported by the relevant results from PROTON
and ELECTRON, which showed that the sustained virological responses
12 weeks after the end of treatment were 90% and 100%, respectively in
people with genotype 3 HCV. The Committee was aware that these
results were from open-label studies in small numbers of people, and that
there was considerable uncertainty around the true magnitude of benefit
of sofosbuvir plus peginterferon alfa and ribavirin in people with
genotype 3 HCV. On balance, however, the Committee concluded that
12 weeks of sofosbuvir plus peginterferon alfa and ribavirin was clinically
more effective than peginterferon alfa and ribavirin alone for 24 weeks in
Page 55 of 104
inducing a sustained virological response in people with genotype 3
treatment-naive HCV.
4.11
The Committee considered the available evidence for sofosbuvir plus
ribavirin in people co-infected with chronic hepatitis C and HIV. It noted
that the interim analysis presented in the company’s original submission
and the regulatory submission was from an ongoing open-label study with
sofosbuvir and ribavirin (PHOTON-1), which included people with
genotype 1, 2 or 3 HCV and HIV who had not had treatment for hepatitis
C, and people with genotype 2 or 3 HCV and HIV who had been treated
before. The Committee subsequently considered the evidence provided
by the company during consultation from the 1910 study (RodriguezTorres et al. [2013]), which compared sofosbuvir plus peginterferon alfa
and ribavirin treatment with peginterferon alfa and ribavirin alone in people
with genotype 1 HCV and HIV. The Committee was aware that the interim
results of both studies suggested that sustained virological responses in
people with HCV and HIV-co-infection were similar to those seen in
people with HCV mono-infection. The Committee understood that the
summary of product characteristics states that people with HCV and HIV
co-infection should have the same sofosbuvir treatment schedule as
people with HCV mono-infection, and concluded that this was appropriate.
4.12
The Committee considered the adverse reactions associated with
sofosbuvir plus ribavirin with and without peginterferon alfa. It noted that
the adverse events reported in the main sofosbuvir clinical studies
(NEUTRINO, FISSION, FUSION, POSITRON and VALENCE) were
generally consistent with those reported in other studies for hepatitis C
treatments. It heard from the clinical experts that sofosbuvir is considered
to have a better safety profile than peginterferon alfa and ribavirin, and
most adverse events reported in the trials were likely to be related to
treatment with peginterferon alfa and ribavirin rather than sofosbuvir. The
Committee concluded that the adverse reactions associated with
sofosbuvir plus ribavirin with or without peginterferon alfa were generally
Page 56 of 104
tolerable and that sofosbuvir was not likely to cause additional adverse
reactions compared with existing treatment regimens.
4.13
The Committee discussed the company’s mixed treatment comparison. It
heard from the company that a network could not be formed for all the
relevant populations and a comparison could be performed only for
genotypes 1, 2 and 3 treatment-naive HCV because of data limitations.
Therefore, results from the mixed treatment comparison were not used to
inform the economic model. The Committee noted that instead, the
company adopted what they described as a conservative approach and
used trial data that reported the highest sustained virological response for
the comparators, including naive comparisons with boceprevir and
telaprevir plus peginterferon alfa and ribavirin for people with genotype 1
HCV. The Committee agreed with the ERG’s view that the company’s
mixed treatment comparison was not robust. Therefore the Committee
concluded that it was reasonable for the company not to use the mixed
treatment comparison to inform its cost-effectiveness analyses.
Cost effectiveness
4.14
The Committee considered the company’s original economic model
provided in the company’s submission, the assumptions underlying the
values of the parameters, and the critique and exploratory analyses
carried out by the ERG. The Committee also considered the revised basecase model submitted by the company in response to the additional
analyses requested by the Committee. The Committee noted that the
company’s model structure differed slightly from that used in previous
technology appraisals for hepatitis C, in that people with mild and
moderate chronic hepatitis C were considered collectively as a population
without cirrhosis, and therefore the model distinguished only between
people with and without cirrhosis. The Committee heard from the clinical
experts that this approach was reasonable and consistent with how
people are currently diagnosed in clinical practice. It heard from the
clinical experts that previously, people had invasive liver biopsies and as a
Page 57 of 104
result their disease was classified as mild, moderate or severe. However,
current practice involves the use of less invasive diagnostic tests that do
not differentiate between mild and moderate disease and can distinguish
only between cirrhosis and non-cirrhosis. The Committee also noted that
the company’s model incorporated the assumption that all people who
had cirrhosis were candidates for liver transplant, and that pre-transplant
patients were therefore included in the modelling presented. The
Committee concluded the approach taken by the company was
appropriate.
4.15
The Committee acknowledged that the ICERs from the company’s original
economic model were for treatment for a combined cohort of people with
and without cirrhosis (hereafter referred to as the ‘combined cohort’). The
Committee heard from clinical experts that it was standard clinical practice
for people with and without cirrhosis to be considered as separate
subgroups, because cirrhosis affects a person’s likelihood of a sustained
virological response. The Committee considered individual ICERs
presented by the company for each genotype by treatment history,
interferon eligibility and cirrhosis status (where available) and noted that
the ICERs were consistently much lower in the subgroups of people with
cirrhosis than in the subgroups of people without cirrhosis. The Committee
also noted that patient numbers underpinning the clinical evidence used in
the economic model were very small for the groups of people with
cirrhosis, and that the sustained virological responses were in some cases
as high as in people without cirrhosis. The Committee heard from clinical
experts that sustained virological responses were historically lower in
people with cirrhosis across all HCV genotypes than in people without
cirrhosis. In addition, the Committee was aware that the summary of
product characteristics states that consideration should be given to
extending sofosbuvir treatment from 12 to 24 weeks in people who have
1 or more factors historically associated with lower response rates to
interferon-based therapies and that 1 of the factors listed is cirrhosis. The
Committee considered that the high sustained virological responses that
Page 58 of 104
were generated from the small numbers of patients in the subgroup of
people with cirrhosis (which resulted in very low ICERs) in each stratified
subgroup should be interpreted with caution. The Committee noted that
the ICERs from the combined cohort appeared artificially low, considering
that most of the group would not have cirrhosis. The Committee
concluded that the consideration of the cost effectiveness of sofosbuvir for
each genotype should take into consideration both the combined cohort
ICER and also the estimated ICERs for treatment in people with and
without cirrhosis.
4.16
The Committee acknowledged that, in response to consultation, the
company presented a revised base-case model for HCV genotypes 1, 3 4,
5 and 6 that incorporated most of its preferred assumptions (see
section 3.64). The company explained and justified deviations from the
Committee’s preferred assumptions, which were included in the revised
model.
4.17
The Committee noted that the revised model included a transition
probability from the sustained virological response cirrhotic health state to
the hepatocellular carcinoma health state (0.0128) using data from
Cardoso et al. as requested by the Committee. In addition, the company
also updated the transition probability from the health state for people with
cirrhosis who have not had a sustained virological response to the
hepatocellular carcinoma health state (0.0631; also from Cardoso et al.)
rather than using the transition probability estimate (0.014) from Fattovich
et al. (1997) that was used in the original model. The Committee heard
from the clinical experts that using both transition probabilities from the
Cardoso et al. study also had face validity because it would allow the
modelling of a relative reduction in the probability that a patient would
progress to hepatocellular carcinoma after having a sustained virological
response. The Committee also heard from the clinical experts that the
Cardoso et al. evidence that a person with cirrhosis who has a sustained
virological response is 4 to 5 times less likely to later have hepatocellular
carcinoma is consistent with the progression to hepatocellular carcinoma
Page 59 of 104
seen in clinical practice. The Committee noted that the Cardoso et al.
transition probabilities were based on a population whose baseline
characteristics were closer to the population seen in clinical practice in
England. However, the Committee also heard from clinical experts that
exploring alternative sources for transition probabilities, such as Fattovich
et al. was appropriate. The Committee concluded that although there is
significant uncertainty about the absolute reduction in the probability of
progression to hepatocellular carcinoma between the sustained virological
response with cirrhosis health state and the health state of cirrhosis
without a sustained virological response, Cardoso et al. was an
acceptable source for transition probabilities for the company’s revised
base-case model. However, the Committee also concluded that it was
plausible that the transition probability for people without a sustained
virological response may lie somewhere between the Cardoso et al. and
Fattovich et al. estimates.
4.18
The Committee considered the impact of using alternative sustained
virological responses for peginterferon alfa and ribavirin in genotype 1
HCV on the results from the revised economic model. The Committee
noted that the company preferred the sustained virological responses for
peginterferon alfa and ribavirin treatment in people with genotype 1 HCV
from McHutchison et al. because it was a larger study and the baseline
characteristics of patients were better matched to the patients in the
pivotal NEUTRINO trial. It also noted that the ERG considered the
estimates from Hadziyannis et al. (2004) to be more relevant because
they were most generalisable to patients with HCV in England. This was
because the study included people with the genotypes most relevant to
the UK population, that is, genotypes 1 and 3 HCV. The Committee heard
from the clinical experts that there is a wide variation in sustained
virological response in clinical practice and that the baseline
characteristics of patients included in each study differed. This had an
impact on the absolute sustained virological responses in these studies.
The clinical experts noted that it was important to consider a range of
Page 60 of 104
alternative sustained virological responses from the evidence base rather
than arbitrarily choosing a single rate from a particular study. The
Committee noted that the sensitivity analyses subsequently presented by
the company showed that the ICERs for sofosbuvir plus peginterferon alfa
and ribavirin compared with peginterferon alfa and ribavirin alone in
people with genotype 1 treatment-naive HCV were £25,000 per QALY
gained using the estimates from Hadziyannis et al. compared with
£17,500 per QALY gained using the estimates from McHutchison et al. On
balance, the Committee concluded that the sustained virological
responses from McHutchison et al. were an acceptable source for
including in its base-case model, but noted that the sustained virological
responses could lie between those provided by the McHutchison and
Hadziyannis data sets.
4.19
The Committee considered the cost of ribavirin used in the company’s
model. The Committee noted that the company used the cost of ribavirin
from the BNF June 2013 in the original model (Copegus; £246.65) and
asked that the company explore the impact of using the price of generic
ribavirin paid by the NHS (£42.05 based on the Department of Health
Commercial Medicines Unit Electronic market information tool) which is
available nationally through contracts negotiated by the NHS Commercial
Medicines Unit. In response to consultation the company included the
generic cost of ribavirin in its revised base-case analysis, but noted that
the Medicines and Healthcare products Regulatory Agency stated that
generic ribavirin should only be used in combination with interferon alfa2b, which only has 3% of the market share in the UK. The Committee
concluded that the generic cost of ribavirin had a small effect on the ICER
as demonstrated by the ERG analysis, but that sensitivity analyses
around the generic costs of comparator treatment were appropriate.
4.20
The Committee discussed the utility values used in the company’s model.
It acknowledged that health-related quality of life was largely assessed in
the clinical trials for sofosbuvir using the SF-36 questionnaire and that
none of the clinical trials collected data using the EQ-5D quality-of-life
Page 61 of 104
measure. The Committee understood that the company obtained SF-36
health-related quality-of-life data at various time points, including
24 weeks after the end of treatment in some trials. The Committee
appreciated that the company tried to be pragmatic in its approach to
modelling the effects of treatment by applying a utility increment of 0.05
(from Wright et al.) after sustained virological response in the company’s
base-case analysis. However, it asked that the company present a
revised base-case model that explored the use of different utility estimates
including more up-to-date estimates from the literature such as VeraLlonch et al. (2013) and estimates from the pivotal clinical trials. The
Committee noted that the company stated it was unable to incorporate the
estimates from the pivotal clinical trials because the data were not
available, but provided a revised base-case model incorporating an
alternative utility increment (0.041; Vera-Llonch et al.) after a sustained
virological response. The Committee noted that using this utility increment
increased the company’s base-case ICERs slightly. The Committee
concluded that although alternative utility estimates from the pivotal
studies would have been preferred, using the utility increment from VeraLlonch et al. in its revised base case was acceptable.
4.21
The Committee discussed the discount rate used in the company’s model
and considered whether this appraisal met the criteria for using a nonreference case discount rate for costs and health benefits that can be
applied in situations when treatment restores people who would otherwise
die or have a very severely impaired life to full or near full health, and
when this is sustained over a very long period (normally at least 30 years),
as described in NICE’s guide to the methods of technology appraisal. The
Committee noted that the company’s base-case analysis used a discount
rate of 3.5% for costs and health benefits in line with the NICE reference
case and that the deterministic sensitivity analysis presented by the
company suggested that the ICERs were particularly sensitive to the
discount rate used. The Committee heard from the clinical experts that a
person who does not have cirrhosis and has a sustained virological
Page 62 of 104
response could be considered cured. However, the Committee was aware
that no data are available beyond the follow-up period from the trials;
therefore evidence supporting the long-term durability of a sustained
virological response is lacking. The Committee also noted that people with
cirrhosis who experience a sustained virological response would not have
their health fully restored. Therefore, the Committee concluded that
sofosbuvir did not meet the criteria for using non-reference case discount
rates, and agreed that the company’s approach to using the standard
discount rate of 3.5% was appropriate.
4.22
The Committee considered whether the cost effectiveness of sofosbuvir
for treating hepatitis C was better assessed for the population as a whole
(that is, using the ‘global’ ICERs presented by the company in response to
consultation, which are weighted by genotype, treatment history and the
presence or absence or cirrhosis, see section 3.66) or separately for each
genotype. The Committee was unconvinced by the global ICER approach
put forward by the company because the evidence from the clinical
experts suggested that in clinical practice treatment is stratified by
genotype, treatment history and other characteristics, including cirrhosis
status. This is because the capacity to benefit from treatment for chronic
hepatitis C differs depending on the patient’s characteristics. The
Committee therefore concluded that it was more appropriate to consider
the clinical and cost effectiveness for each relevant subgroup of patients
separately in the company’s base-case analyses.
Genotype 1
Treatment-naive, interferon eligible
4.23
The Committee considered the cost effectiveness of sofosbuvir plus
peginterferon alfa and ribavirin for people with genotype 1 treatment-naive
HCV who are eligible for interferon treatment. The Committee noted that
the ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks
compared with peginterferon alfa and ribavirin alone for 48 weeks was
less than £17,500 per QALY gained. The Committee noted that the ICERs
Page 63 of 104
for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared
with response-guided treatment with boceprevir plus peginterferon alfa
and ribavirin and telaprevir plus peginterferon alfa and ribavirin were
£10,300 and £15,400 per QALY gained, respectively. The Committee
noted that when stratified by the presence or absence of cirrhosis, the
ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks
compared with peginterferon alfa and ribavirin for 48 weeks were £5400
and £25,200 per QALY gained, respectively. The ICERs for sofosbuvir
plus peginterferon alfa and ribavirin for 12 weeks compared with
boceprevir plus peginterferon alfa, when stratified by the presence or
absence of cirrhosis, were £2800 and £14,300 per QALY gained,
respectively. The ICERs for sofosbuvir plus peginterferon alfa and
ribavirin for 12 weeks compared with telaprevir plus peginterferon alfa,
when stratified by the presence or absence of cirrhosis, were £4200 and
£22,300 per QALY gained, respectively. The Committee also considered
the ERG’s exploratory analyses (see section 3.76). The ERG’s resulting
ICER for the combined cohort for sofosbuvir plus peginterferon alfa and
ribavirin for 12 weeks compared with peginterferon alfa and ribavirin alone
for 48 weeks was just over £30,000 per QALY gained. The Committee
believed that this ICER represented the upper limit of what could be
considered to plausible, but that the ICERs for sofosbuvir plus
peginterferon alfa and ribavirin for 12 weeks compared with responseguided boceprevir and telaprevir plus peginterferon alfa and ribavirin
treatment, which are the standard of care in the NHS, were £12,200 and
£18,700 per QALY gained. The Committee concluded that sofosbuvir plus
peginterferon alfa and ribavirin was cost effective for people with
treatment-naive genotype 1 HCV.
Treatment-experienced, interferon eligible
4.24
peginterferon alfa and ribavirin for 12 weeks compared with standard of
care in people with genotype 1 treatment-experienced HCV for whom
interferon is suitable. The Committee acknowledged the uncertainty in the
Page 64 of 104
ICER for the population who have treatment-experienced HCV in the light
of the lack of clinical evidence, but noted that there are very few treatment
options for these patients, who have a high unmet need. The Committee
noted that the estimate of sustained virological response in the treatmentexperienced population provided by the company was accepted by the
European Medicines Agency and clinical experts. The Committee noted
that the ICERs for sofosbuvir plus peginterferon alfa and ribavirin for
12 weeks compared with peginterferon alfa and ribavirin for 48 weeks
(£12,600 per QALY gained), boceprevir plus peginterferon alfa and
ribavirin (£700 per QALY gained), and telaprevir plus peginterferon alfa
and ribavirin (£8200 per QALY gained) for the combined cohort of people
with and without cirrhosis could be considered cost effective although
ICERs stratified by cirrhosis status were not available. The Committee
considered that if the relative proportion of people with and without
cirrhosis was similar to that observed in the group with treatment-naive
HCV, then it would be likely that the stratified ICERs for sofosbuvir plus
alfa and ribavirin alone for 48 weeks would be cost effective for people
with and without cirrhosis even when taking into account the assumptions
in the ERG’s exploratory analyses, which would increase the ICERs
further. The Committee also noted that the stratified ICERs for sofosbuvir
plus peginterferon alfa and ribavirin for 12 weeks compared with
response-guided boceprevir and telaprevir plus peginterferon alfa and
ribavirin treatment would be even lower for these groups, and that these
2 treatment regimens are the standard of care in the NHS. The Committee
concluded that sofosbuvir plus peginterferon alfa and ribavirin is a costeffective treatment option for people with genotype 1 treatmentexperienced HCV who are eligible for interferon treatment.
Treatment-naive, interferon ineligible
4.25
ribavirin for 24 weeks compared with standard of care (no treatment) in
people with genotype 1 treatment-naive HCV for whom interferon is
Page 65 of 104
unsuitable. It noted that the ICER for sofosbuvir and ribavirin compared
with no treatment for this population was £47,600 per QALY gained. In
response to consultation, the company stated that although it is necessary
to have options for this subgroup of patients for whom interferon treatment
is unsuitable and who have a high unmet need, it is anticipated that the
number of people in this group having 24 weeks of sofosbuvir plus
ribavirin would be extremely low. The Committee also heard from the
company that it was not expecting people with genotype 1 HCV who are
interferon eligible to be given the option of the 24 week interferon-free
sofosbuvir regimen. The Committee concluded that although the number
of people with genotype 1 treatment-naive HCV for whom interferon is
unsuitable is potentially small, the high ICER for sofosbuvir plus ribavirin
alone compared with no treatment for this population does not represent a
cost-effective use of NHS resources and could not be recommended.
Treatment-experienced, intolerant to or ineligible for interferon treatment
4.26
The Committee considered the lack of evidence for sofosbuvir plus
ribavirin for 24 weeks compared with the standard of care (no treatment)
in the subgroup of people with genotype 1 treatment-experienced HCV
who are intolerant to or ineligible for interferon treatment. However,
considering the Committee had accepted the ICERs generated using the
sustained virological responses recognised by the US Food and Drug
Administration (FDA) for the genotype 1 treatment-experienced HCV
population who are eligible for interferon, the Committee took a pragmatic
view on how to establish an estimated ICER for this population. The
starting point for the Committee was the ICER of £47,600 per QALY
gained (that is the ICER for people with genotype 1 treatment-naive HCV,
for whom interferon is unsuitable). Assuming that the relative difference
between the ICERs in the treatment-naive and treatment-experienced
HCV groups seen in other genotypes also applies to genotype 1 HCV, the
Committee would expect that the ICERs for the genotype 1 treatmentexperienced HCV group would likely be slightly lower than the ICER for
people in the genotype 1 treatment-naive HCV group. When stratified by
Page 66 of 104
the presence or absence of cirrhosis, the ICERs would be likely to
increase in the subgroup without cirrhosis and decrease in the subgroup
with cirrhosis, in a similar proportion to that seen in the subgroup of
people with treatment-naive genotype 1 HCV for whom interferon is
unsuitable. However, the ICERs would still remain high. The Committee
noted that if the assumptions used in the ERG’s exploratory analyses
were applied, the ICERs would increase in the combined cohort as well as
in the subgroups with and without cirrhosis. The Committee was aware
that people with genotype 1 treatment-experienced HCV for whom
interferon is unsuitable are a group with a high unmet need. However, the
Committee concluded that based on the very uncertain evidence
presented and the high ICERs, treatment with sofosbuvir plus ribavirin for
24 weeks does not represent a cost-effective use of NHS resources for
people with genotype 1 treatment-experienced HCV who are intolerant to
or ineligible for interferon treatment and therefore could not be
recommended in this group.
Genotype 2
4.27
ribavirin compared with peginterferon alfa and ribavirin for 24 weeks in
people with genotype 2 HCV who are eligible for interferon treatment, or
no treatment in people who are intolerant or ineligible for treatment with
interferon. The Committee noted that sofosbuvir plus peginterferon alfa
and ribavirin does not have a marketing authorisation for treating
genotype 2 HCV. The Committee noted that the ICER from the company’s
original base-case model for sofosbuvir and ribavirin compared with
peginterferon alfa and ribavirin alone was approximately £46,300 per
QALY gained in people who are eligible for treatment with interferon and
who have treatment-naive HCV, and £12,500 per QALY gained in people
who have treatment-experienced HCV and are eligible for treatment with
interferon. The ICER for sofosbuvir and ribavirin compared with no
treatment for people who are intolerant to or ineligible for interferon was
£8200 per QALY gained for people with treatment-naive HCV, and £8600
Page 67 of 104
per QALY gained for people with treatment-experienced HCV. The
Committee concluded that sofosbuvir plus ribavirin was not a costeffective use of NHS resources in adults with genotype 2 treatment-naive
HCV who are eligible for treatment with interferon. However, the
Committee concluded that sofosbuvir plus ribavirin was a cost-effective
use of NHS resources for adults with genotype 2 HCV who are eligible for
treatment with interferon and who have had treatment for HCV and for
adults with genotype 2 HCV who are intolerant or ineligible for interferon
treatment, regardless of their treatment history.
Genotype 3
4.28
alfa and ribavirin for 48 weeks in people with genotype 3 treatment-naive
HCV who are eligible for treatment with interferon. The Committee noted
from the company’s revised base case that the combined cohort ICER
(with and without cirrhosis) for sofosbuvir plus peginterferon alfa and
ribavirin compared with peginterferon alfa and ribavirin alone for this
population was approximately £21,900 per QALY gained. The Committee
noted that when stratified by cirrhosis status, the ICER for people with
treatment-naive HCV without cirrhosis who are eligible for treatment with
interferon was approximately £40,600 per QALY gained, whereas the
ICER for people with cirrhosis was approximately £6600 per QALY
gained. The Committee noted that the ICERs for the subgroups of
patients with or without cirrhosis were highly uncertain due to the small
patient numbers included in the studies. The Committee noted that the
effect of using the combined cohort analysis which includes a larger
subgroup without cirrhosis and a small subgroup with cirrhosis, resulted in
a combined cohort ICER that was artificially low (£21,900 per QALY
gained). The Committee considered that despite this uncertainty there
was more confidence around the ICER for the subgroup with cirrhosis
Page 68 of 104
because the treatment remained cost effective despite using a variety of
assumptions including those suggested by the ERG in its exploratory
analyses. The Committee also acknowledged that people with cirrhosis
are in greater need of treatment than those without cirrhosis. Therefore,
the Committee concluded that sofosbuvir plus peginterferon alfa and
ribavirin for 12 weeks could be considered a cost-effective use of NHS
resources in people with genotype 3 treatment-naive HCV who are eligible
for interferon treatment and who have cirrhosis, but it was not a costeffective use of NHS resources in people who do not have cirrhosis.
4.29
The Committee noted that the marketing authorisation for sofosbuvir
allows 24 weeks dual therapy with sofosbuvir plus ribavirin as an
alternative to 12 weeks with sofosbuvir plus peginterferon alfa and
ribavirin for people with genotype 3 HCV who are eligible for treatment
with interferon. The Committee considered the exploratory analyses
carried out by the company modelling the effect on the revised base-case
ICERs of varying the proportion of people with genotype 3 HCV receiving
sofosbuvir plus ribavirin for 24 weeks in people eligible for treatment with
interferon (see section 3.75). The Committee noted that the scenario
analysis presented by the company in which 100% of people with
treatment naive genotype 3 HCV received sofosbuvir plus ribavirin for 24
weeks compared with peginterferon plus ribavirin for 24 weeks resulted in
an ICER of £47,000 per QALY gained. The ICER for sofosbuvir plus
peginterferon alfa and ribavirin for 12 weeks treatment compared with
peginterferon and ribavirin treatment for 24 weeks increased from
approximately £21,900 per QALY gained to approximately £22,400 and
£27,100 per QALY gained when it was assumed that 2% and 20% had
sofosbuvir and ribavirin for 24 weeks treatment in the population with
treatment-naive HCV who are eligible for interferon. The Committee noted
that when stratified by cirrhosis status, the revised base-case ICER for
sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks treatment
compared with peginterferon and ribavirin treatment for 24 weeks
increased in the subgroup without cirrhosis to £41,700 and £51,300 per
Page 69 of 104
QALY gained when it was assumed that 2% and 20% had sofosbuvir and
ribavirin in the treatment-naive population. In the subgroup with cirrhosis,
the ICER increased to £6800 and £8400 per QALY gained using the same
assumptions. The Committee concluded that the duration of treatment
with sofosbuvir had a considerable effect on the ICERs in people with
genotype 3 HCV, although it heard from the company, clinical experts and
commissioners that sofosbuvir and ribavirin treatment for 24 weeks would
only be appropriate for people ineligible for interferon therapy.
4.30
alfa and ribavirin for 48 weeks in people with genotype 3 treatmentexperienced HCV who are eligible for treatment with interferon. The
Committee noted that the company’s revised base-case ICER for the
combined cohort was £13,900 per QALY gained. When stratified by
cirrhosis status, the ICER for people without cirrhosis was £18,600 per
QALY gained, whereas the ICER for people with cirrhosis was £6300 per
QALY gained. The Committee was aware that these ICERs were also
uncertain, due to small patient numbers included in the studies, and that
sustained virological responses were identical for people in the subgroups
with and without cirrhosis, which is clinically unlikely due to the poorer
sustained virological responses usually seen in people with cirrhosis. The
Committee was willing to accept this uncertainty because the ICERs were
within the range it could consider a technology might be cost-effective in
the group without cirrhosis and even lower in the group with cirrhosis. The
ICERs remained in this range when the ERG’s exploratory assumptions
were used. The Committee acknowledged that this subgroup also has no
further treatment options and can be considered to have a high unmet
need. The Committee therefore concluded that sofosbuvir plus
peginterferon alfa and ribavirin was a cost-effective use of NHS resources
in people with genotype 3 treatment-experienced HCV who were eligible
for interferon treatment.
Page 70 of 104
4.31
As with the treatment naive, interferon eligible group with genotype
3 HCV, the Committee considered the exploratory analyses carried out by
the company that modelled the effect on the revised base-case ICERs of
increasing the proportion of people with treatment-experienced genotype
3 HCV receiving sofosbuvir plus ribavirin for 24 weeks (see section 3.75).
The ICER for sofosbuvir plus ribavirin for 24 weeks compared with
peginterferon plus ribavirin for 48 weeks in people with treatment
experienced genotype 3 HCV who are eligible for interferon treatment
increased to £48,300 per QALY gained. The ICER for sofosbuvir plus
alfa and ribavirin for 48 weeks also increased for the population for whom
interferon therapy is suitable and who had treatment-experienced HCV,
from approximately £13,900 per QALY gained to approximately £14,500
and £19,900 per QALY gained when it was assumed that 2% and 20%
had sofosbuvir and ribavirin. The Committee concluded that the duration
of treatment with sofosbuvir had a considerable effect on the ICERs in
people with genotype 3 HCV, and it agreed with the company, clinical
experts and commissioners that sofosbuvir and ribavirin treatment for
24 weeks would only be appropriate for people ineligible for interferon
therapy.
Treatment-naive, interferon ineligible
4.32
The Committee considered the cost effectiveness of sofosbuvir and
ribavirin for 24 weeks compared with no treatment in people with
genotype 3 treatment-naive HCV who are ineligible for treatment with
interferon. The Committee noted that the company’s revised base-case
ICER for this population was £21,000 per QALY gained, which was
calculated based on sustained virological responses seen in VALENCE.
The Committee noted that the VALENCE study was unblinded when
treatment was extended for all people with genotype 3 HCV. Therefore it
was of poor quality and open to potential bias. The Committee noted that
when the population was stratified by cirrhosis status, the ICER for
sofosbuvir plus ribavirin was £28,000 per QALY gained for people without
Page 71 of 104
cirrhosis (which increased to £32,000 per QALY gained using the ERG
assumptions) and £10,500 per QALY gained for people with cirrhosis. The
Committee concluded that given the uncertainty around the ICER in the
group without cirrhosis and the possibility that the ICER may be over
£32,000 per QALY gained, it could not recommend sofosbuvir plus
ribavirin treatment in people with genotype 3 treatment-naive HCV without
cirrhosis who are ineligible for interferon treatment. Because the ICER in
the subgroup of people with cirrhosis remained low (£15,100 per QALY
gained), even when using the ERG’s exploratory assumptions, the
Committee concluded that sofosbuvir plus ribavirin is cost effective for
people with genotype 3 treatment-naive HCV who have cirrhosis.
Treatment-experienced, interferon ineligible
4.33
The Committee considered the cost effectiveness of sofosbuvir and
ribavirin for 24 weeks compared with no treatment in people with
treatment-experienced genotype 3 HCV who are intolerant to or ineligible
for treatment with interferon. The Committee considered that this group
would represent a very small number of patients in the NHS. The
Committee considered the company’s revised base-case ICER of
approximately £27,500 per QALY gained for the combined cohort of
people with and without cirrhosis. The Committee noted that this ICER
was also based on the sustained virological response rates observed in
VALENCE, a study that the Committee considered to be of low quality and
open to potential bias (see sections 3.16 and 4.32). When the ICERs were
stratified by cirrhosis status, the company’s revised base-case ICER for
the subgroup without cirrhosis was £31,400 per QALY gained (£35,000
per QALY gained using the assumptions from the ERG exploratory
analyses). Due to the uncertainty around the ICER and the possibility that
the ICER was over £35,000 per QALY gained, the Committee concluded
that sofosbuvir plus ribavirin was not a cost-effective use of NHS
resources in people with treatment-experienced genotype 3 HCV without
cirrhosis who are intolerant to or ineligible for interferon treatment. The
Committee noted that the company’s revised base-case ICER for
Page 72 of 104
sofosbuvir plus ribavirin for 24 weeks compared with no treatment for
people with cirrhosis was £19,200 per QALY gained (£29,700 per QALY
gained when using the assumptions from the ERG exploratory analyses).
The Committee considered the high unmet need of this subgroup for
whom there are currently no other licensed treatment options. The
Committee recognised the uncertainty in the evidence base for people
with treatment-experienced genotype 3 HCV who have cirrhosis and are
intolerant to or ineligible for interferon. However, on balance, it concluded
that it would be consistent with its other recommendations for people with
genotype 3 HCV to recommend sofosbuvir plus ribavirin for 24 weeks for
people with cirrhosis and that this could be considered a cost-effective
use of NHS resources, because the true ICER was likely to be between
the company’s revised base case and the ERG’s exploratory estimates.
Genotypes 4, 5 and 6
4.34
The Committee considered the company’s original base-case ICER for
with peginterferon alfa and ribavirin for 48 weeks of approximately
£26,800 per QALY gained in people with genotype 4, 5, or 6 treatmentnaive HCV, for whom interferon is suitable. The Committee noted that the
ICER was based on a naive comparison of the sustained virological
responses 12 weeks after the end of treatment for sofosbuvir plus
peginterferon alfa-2a and ribavirin observed in NEUTRINO and the
sustained virological responses 24 weeks after the end of treatment with
peginterferon alfa-2b and ribavirin observed in Manns et al. (2001). The
Committee heard from clinical experts and the company that peginterferon
alfa 2a and peginterferon alfa 2b were assumed to be equally efficacious
and that sustained virological response 24 weeks after the end of
treatment was essentially equivalent to sustained virological response
12 weeks after the end of treatment. The Committee noted that of the
35 people with genotype 4, 5 or 6 in the NEUTRINO study, 100% of the
Page 73 of 104
33 people without cirrhosis achieved a sustained virological response
compared with 50% of the 2 people with cirrhosis. However in Manns et
al., the subgroup without cirrhosis had a sustained virological response of
50% (as calculated by the company, based on the relative difference in
sustained virological response between people without cirrhosis and
people with cirrhosis in the studies in genotype 1, 2 and 3 HCV) and the
subgroup with cirrhosis had a sustained virological response of 38.6%.
The Committee noted that the difference in sustained virological
responses between the sofosbuvir plus peginterferon alfa and ribavirin
arm and the peginterferon alfa plus ribavirin alone arm of the model was a
key driver of the ICER.
4.35
During consultation, the company presented the Committee with
additional analyses for people with genotype 4, 5 or 6 HCV, which
included alternative sustained virological responses for peginterferon alfa
plus ribavirin from studies identified in a systematic review of studies in
genotypes 4, 5 and 6 HCV and the impact of using different sustained
virological responses on the ICER. The Committee noted that the studies
were exclusively European (because the company considered the patient
characteristics to be more relevant to patients in the UK) whereas the
ERG had considered studies from the Middle East and Egypt to be an
important source of data because these studies included larger numbers
of patients. The Committee noted that the sustained virological responses
for peginterferon alfa plus ribavirin in the European studies ranged from
33% (Zeuzem et al. [2005]) to 77% (Fried et al. [2002]), which spanned
the range of sustained virological responses seen in the studies identified
by the ERG. The Committee considered the revised base-case ICER of
£27,500 per QALY gained presented by the company for sofosbuvir plus
peginterferon alfa and ribavirin compared with peginterferon alfa and
ribavirin (using the sustained virological responses from Manns et al.
[2001] for the latter) in people with genotype 4, 5 or 6 HCV. The
Committee noted that the company varied the sustained virological
response for peginterferon alfa and ribavirin using Zeuzem et al. and Fried
Page 74 of 104
et al. but noted that sustained virological responses were not available by
cirrhosis status. Therefore the company applied the same sustained
virological response for people with and without cirrhosis. The ICERs for
with peginterferon alfa plus ribavirin for 48 weeks using Zeuzem et al. and
Fried et al. were £19,148 and £244,387 per QALY gained, respectively.
The Committee considered that a sustained virological response of 77%
for 48 weeks of treatment with peginterferon alfa and ribavirin was
improbable. The Committee considered the ERG’s exploratory analyses,
in which the sustained virological responses in the peginterferon alfa and
ribavirin arm were based on a weighted average of the responses
reported in the individual studies. The ERG used a sustained virological
response of 54.8% from the European studies (which included the studies
by Manns et al. and Lindsay et al.) which led to an ICER of approximately
£39,100 per QALY gained. The Committee considered this to be the most
relevant ICER because it was based on studies with populations that were
most similar to patients in England and was generated using the
Committee’s preferred assumptions (see section 4 15). The Committee
noted that the sustained virological responses for peginterferon alfa plus
ribavirin for 48 weeks in people with genotype 4, 5 or 6 HCV were higher
than those reported for people with genotype 1 HCV, providing indirect
evidence that people with genotype 4 HCV are not more difficult to treat.
The Committee concluded that the ICER of £39,100 per QALY gained for
with peginterferon alfa plus ribavirin for 48 weeks using the ERG’s
calculated sustained virological response was the most plausible,
although there remained considerable uncertainty about the ICER,
because of the small number of people included in the NEUTRINO study.
4.36
The Committee considered comments received during consultation that
recommending sofosbuvir plus peginterferon alfa and ribavirin only for a
proportion of people with genotype 1, 2 or 3 HCV, but not for anyone with
genotype 4, 5 or 6 HCV could potentially be interpreted as indirect
Page 75 of 104
discrimination. It heard from consultees that this was because a larger
proportion of minority ethnic groups, people with HIV co-infection and
haemophilia are represented in the genotype 4, 5 and 6 HCV population.
In light of NICE’s legal obligation to promote equality, the Committee
considered the additional evidence provided by the company that included
family origin by HCV genotype, and the prevalence of HIV and HCV coinfection and HCV infection in people with haemophilia. The Committee
noted that the family origin evidence was self-reported (and could
therefore not be verified), and used broad categories. The Committee
therefore considered this evidence to be uncertain, although it noted the
anecdotal evidence provided by other consultees that minority ethnic
groups are more highly represented in the genotype 4, 5 and 6 HCV
population. The Committee considered the commercial-in-confidence
evidence presented by the company about the genotype distribution of
HCV in people with HCV and HIV co-infection and agreed that a
disproportionate number of people had genotype 4 HCV and HIV coinfection compared with the overall population of people with HCV in
England. The Committee noted that the evidence presented by the
company suggested that 96% of people with haemophilia and HCV had
genotype 1, 2 or 3 HCV, and 4% had genotype 4 or 5 because no patients
were identified with genotype 6 HCV and haemophilia. The Committee
noted that the distribution of HCV genotypes in people with haemophilia
presented by the company was actually similar to the overall population of
people with HCV in England. The Committee concluded that there did not
appear to be a disproportionate percentage of people with haemophilia
who had genotype 4 HCV in England. The Committee noted that the
ICERs for sofosbuvir for people with genotype 4, 5 or 6 HCV for the
combined cohort (people with and without cirrhosis) were very high.
However, it agreed that, in the light of evidence on the higher
representation of minority ethnic groups and HIV co-infection in these
genotypes, further consideration should be given to whether anything
could be done to remove or reduce the disproportionate impact for the
protected groups.
Page 76 of 104
4.37
The Committee noted that unlike genotype 1 HCV, people with
genotype 4, 5 or 6 HCV currently only have peginterferon alfa and
ribavirin for 48 weeks as a treatment option. The Committee considered
that the people with the highest unmet need within this population are
those with cirrhosis, because their disease is less likely to respond to
treatment with peginterferon alfa and ribavirin for 48 weeks. Although the
sustained virological response seen in people with genotype 4, 5 or 6
HCV with cirrhosis was 50% in NEUTRINO, the Committee noted that this
was based on 2 patients; 1 who had a sustained virological response and
1 who did not. As with some of the other genotypes, the Committee used
a pragmatic approach in estimating an ICER for sofosbuvir for the group
of people with genotype 4, 5 or 6 with cirrhosis. Using the starting point for
the ICER (calculated by the ERG) as £39,100 per QALY gained, the
Committee considered whether the ICER for genotypes 4, 5 and 6
responded in a similar manner as for other genotypes, that is, whether it
would be significantly lower for treatment in people with cirrhosis than in
people without cirrhosis. The Committee considered that it is plausible
that the ICER for treatment in people with genotypes 4, 5 or 6 treatmentnaive HCV with cirrhosis could be within the range that is normally
accepted as being cost effective, that is between £20,000 and £30,000
per QALY gained, and that the ICER for treatment in people with
genotypes 4, 5 or 6 treatment-naive HCV without cirrhosis is likely to be
greatly in excess of the £39,100 per QALY gained estimated by the ERG
for the combined cohort. Therefore, taking into consideration the potential
equality issues raised about genotypes 4, 5 and 6 HCV, the high unmet
need and the lack of treatment options for people with cirrhosis, the
Committee considered it was reasonable to conclude that sofosbuvir plus
peginterferon alfa and ribavirin for treating people with genotype 4, 5 or 6
treatment-naive HCV who have cirrhosis was a cost-effective use of NHS
resources.
Page 77 of 104
4.38
The Committee considered cost-effectiveness evidence presented for
people with genotypes 4, 5 or 6 treatment-experienced HCV, for whom
interferon is suitable. The Committee noted that the company did not
provide an ICER for treatment in this group and that an estimate for this
ICER could only be based on the ICER in people who are eligible for
interferon who have not had treatment before. The Committee
acknowledged that there is even more uncertainty in the ICER for
treatment in the population who have treatment-experienced HCV in the
light of the lack of clinical evidence, but noted that there are very few
treatment options for these patients, who have an even higher unmet
need than people who have never been treated before. Considering the
uncertainty in the evidence, but also taking into consideration the potential
equality issues raised for people with genotype 4, 5 or 6 HCV, the
Committee took a pragmatic view on how to establish an estimated ICER
for this population. The Committee noted that sofosbuvir plus
peginterferon alfa and ribavirin was recommended for genotype 1
treatment-experienced HCV on the basis of unmet need and approval
from the FDA based on a sustained virological response that was
calculated from the population who had not had treatment before.
Therefore, the Committee concluded that a similar approach could be
used for people with genotype 4, 5 and 6 treatment-experienced HCV.
Although sustained virological responses are typically lower in the
treatment-experienced populations, the costs associated with disease
progression and a comparison with no treatment mean that the ICERs for
sofosbuvir in treatment-experienced people are consistently lower than
the ICERs for sofosbuvir in people who have not had treatment. Using the
starting point for the ICER (calculated by the ERG) as £39,100 per QALY
gained for people with genotype 4, 5 or 6 treatment-naive HCV, the
Committee considered that it was plausible that the ICER in genotypes 4,
5 or 6 treatment-experienced HCV with cirrhosis could also be within the
range that is normally accepted as being cost effective, that is between
£20,000 and £30,000 per QALY gained. The Committee concluded that
Page 78 of 104
for all these reasons, sofosbuvir plus peginterferon alfa and ribavirin for
treating people with genotype 4, 5 or 6 treatment-experienced HCV who
have cirrhosis could be considered a cost-effective use of NHS resources.
Interferon unsuitable
4.39
The Committee considered the group of people with genotype 4, 5 or 6
HCV, for whom interferon therapy is unsuitable. The Committee noted that
the company did not provide an ICER for sofosbuvir plus ribavirin in this
population. The starting point for the Committee was the only costeffectiveness evidence provided for this population, namely the ICER of
£39,100 per QALY gained for people with genotype 4, 5 or 6 HCV, for
whom interferon therapy is suitable. The Committee noted that the ICER
for sofosbuvir plus ribavirin compared with no treatment in people with
treatment naive genotype 1 HCV who were not eligible for interferon was
more than double the ICER for sofosbuvir plus peginterferon and ribavirin
compared with peginterferon and ribavirin in people who were interferon
eligible. The Committee anticipated that the ICERs for sofosbuvir plus
ribavirin in people with genotype 4, 5 or 6 HCV, for whom interferon
therapy is unsuitable, would increase significantly due to the fact that
treatment would be offered for 24 weeks instead of 12 weeks and this was
likely to increase further using the ERG’s exploratory assumptions. The
Committee considered that, based on the lack of evidence provided for
these genotypes, it was necessary to make a value judgment. Although
people with genotype 4, 5, or 6 HCV represent a small proportion of the
total HCV population in England, it is still an important group with a high
unmet need. The Committee reflected on the quality of evidence and the
level of uncertainty, in addition to the very high costs associated with
sofosbuvir plus ribavirin treatment for 24 weeks. The Committee
concluded that treatment with sofosbuvir plus ribavirin for 24 weeks was
not a cost-effective use of NHS resources and could not be recommended
for adults with genotype 4, 5 or 6 HCV, for whom interferon therapy is not
suitable.
Page 79 of 104
4.40
The Committee noted the company presented separate economic
analyses for people co-infected with HCV and HIV based on interim
results from the PHOTON-1 study and the 1910 study. The Committee
was aware the PHOTON-1 study provided results for people with
genotypes 1, 2 or 3 HCV treated for 12 or 24 weeks with sofosbuvir and
ribavirin and the 1910 study provided results for people with genotypes 1
or 3 HCV treated with sofosbuvir plus peginterferon alfa and ribavirin for
12 weeks. The Committee was aware that, other than incorporating higher
transition probabilities from the non-cirrhotic to the compensated cirrhosis
state, the modelling did not differ for the mono-infected and co-infected
populations. The Committee noted the ERG comment that there were
differences in patient characteristics and outcomes that were not taken
into account in the company’s model. On balance, the Committee
concluded that, based on the evidence presented and considered for this
population, it was reasonable to include the group of people co-infected
with HCV and HIV in the recommendations for the mono-infected group.
However, the Committee agreed with the ERG that there were legitimate
concerns about the modelling for the HIV and HCV co-infected group, and
that future economic analyses should be presented separately for this
population.
4.41
The Committee considered the concern expressed in comments received
during consultation that some inexperienced clinicians may want to offer
sofosbuvir and ribavirin for 24 weeks to people with genotypes 1, 4, 5 or 6
HCV who are interferon eligible in order to avoid the possible adverse
effects associated with interferon treatment. The Committee heard from
the company that the sustained virological responses with sofosbuvir plus
peginterferon alfa and ribavirin in these genotypes are superior to those
achieved using sofosbuvir and ribavirin alone. It also heard from company
representatives that sofosbuvir plus ribavirin alone was only licensed for
people in urgent need of care with genotype 1, 4, 5, or 6 HCV in whom
interferon was contraindicated (as described in the summary of product
characteristics) or whose disease did not have an adequate response to
Page 80 of 104
interferon treatment. The company representatives agreed that sofosbuvir
and ribavirin would be regarded as a second-line option and the decision
to use dual therapy should only be made by clinicians experienced in
treating hepatitis C, preferably after discussion by a multidisciplinary team.
However, the Committee concluded that the concerns expressed during
consultation were no longer relevant in light of the Committee’s decision
that sofosbuvir, in combination with ribavirin, should not be recommended
for treating adults with genotype 1, 4, 5 or 6 chronic hepatitis C who are
interferon intolerant or ineligible (see sections 1.1 and 4.25, 4.26 and
4.39).
4.42
The Committee noted a comment received from the public during the
second consultation stating that it was potentially more cost effective to
treat hepatitis C in people with haemophilia than people without
haemophilia due to the large expense associated with treating
haemophilia and the additional expenses due to monitoring liver damage
in that group. The Committee noted that the clinical trials excluded
patients with haemophilia and no clinical evidence or cost-effectiveness
analysis had been presented specifically for people with haemophilia and
HCV. Therefore the Committee concluded that no evidence-based
decision or modelling would be possible, and therefore no separate
recommendation could be made specifically for this patient group.
4.43
The Committee discussed comments from the patient experts indicating
that in practice the availability of treatment for people with chronic
hepatitis C who use injectable drugs was limited, which could represent a
potential equality consideration. The Committee heard from the clinical
experts that treatment for these people is considered on an individual
basis because of concerns about safety and treatment adherence, but
that clinicians would like to offer sofosbuvir to people using injectable
drugs, taking into account any precautions in the summary of product
characteristics. The Committee acknowledged that access to treatment for
this patient group was an issue related to implementation and could not
be addressed through technology appraisal recommendations. However,
Page 81 of 104
the Committee concluded that although people who use injectable drugs
were not represented in the pivotal clinical trials for sofosbuvir, based on
the current evidence available, there was no reason to deny them access
to treatment; therefore any recommendations on the use of sofosbuvir
would be irrespective of injectable drug use.
4.44
The Committee discussed whether sofosbuvir could be considered an
innovative treatment, providing a step change in the treatment of chronic
hepatitis C. The Committee agreed that sofosbuvir offers the possibility of
shortened interferon-based treatment regimens, or treatment without
interferon therapy in some circumstances, which is particularly important
and a major development in the current clinical management of chronic
hepatitis C. The Committee therefore accepted that sofosbuvir is a
valuable new therapy for treating chronic hepatitis C. The Committee
agreed with the clinical experts and patient experts that there were other
benefits to patients (such as relief of loss of cognitive ability in people with
HCV) and public health benefits (such as reduced transmission of HCV)
that were not captured in the QALY calculation and that, if taken into
account, would decrease the ICERs.
4.45
During consultation, although a number of consultees noted the urgent
need for guidance on the use of sofosbuvir, a comment was also received
from NHS England, who is currently responsible for the commissioning of
hepatitis C treatment, that it would not be possible to implement the
recommendations in this guidance within 3 months. The Committee were
in agreement that there may be increased demand for treatment following
positive recommendations, but were not presented with evidence on the
likely magnitude of this and considered that some patients may prefer to
wait for NICE guidance on other interferon-free treatments for chronic
hepatitis C before they seek treatment. The Committee highlighted that it
would be reasonable for NICE to reflect on whether the standard 3 month
implementation period is appropriate. The Committee noted that
consultees were interested in the relative cost effectiveness of sofosbuvir
compared with other agents in guidance development (although this did
Page 82 of 104
not fall within the scope of this appraisal). It therefore concluded that a
1 year review date for the guidance would be appropriate.
Summary of Appraisal Committee’s key conclusions
TAXXX
Appraisal title: Sofosbuvir for treating chronic
hepatitis C
Section
Key conclusions
Genotype 1
The Committee considered sofosbuvir plus ribavirin with or without
peginterferon alpha to be clinically effective in people with genotype 1
treatment-naive and experienced HCV. The Committee considered
treatment with sofosbuvir plus peginterferon alfa and ribavirin compared
with peginterferon alfa and ribavirin in people who were eligible for
interferon treatment to be cost effective regardless of previous treatment
(with ICERs of approximately £17,500 per QALY gained in treatment-naive
patients).The Committee also considered sofosbuvir plus peginterferon alfa
and ribavirin to be cost effective compared with boceprevir plus
peginterferon and ribavirin, and telaprevir in combination with peginterferon
alfa and ribavirin (ICERs of approximately £10,300 and £15,400 per QALY
gained respectively). The Committee considered sofosbuvir plus
peginterferon alfa and ribavirin to be cost effective in people with treatmentexperienced HCV compared with peginterferon and ribavirin, boceprevir
and ribavirin and telaprevir and ribavirin with ICERs of approximately
£12,600, £700 and £8200 per QALY gained respectively.
Sofosbuvir plus ribavirin was not recommended in people for whom
interferon was unsuitable (regardless of previous treatment) because of the
high ICER compared with standard care (no treatment), which was in
excess of £47,600 per QALY gained in the combined population of people
with and without cirrhosis.
Genotype 2
The Committee considered sofosbuvir plus ribavirin to be clinically more
effective than peginterferon alfa and ribavirin in people with genotype 2
HCV who were eligible for treatment with peginterferon alfa. Sofosbuvir plus
ribavirin was not recommended in the group with treatment-naive HCV
because of the high ICER of £46,300 per QALY gained but was
recommended in people with treatment-experienced HCV because of the
ICER of £12,500 per QALY gained.
The Committee considered sofosbuvir plus ribavirin to be clinically effective
and cost effective compared with no treatment in people for whom
treatment with interferon was unsuitable regardless of treatment experience
(with ICERs of approximately £8200 and £8600 per QALY gained
respectively).
Genotype 3
The Committee considered the extended treatment duration (24 weeks) of
sofosbuvir plus with ribavirin to be clinically effective compared with
peginterferon alfa and ribavirin. The Committee considered sofosbuvir plus
peginterferon alfa and ribavirin to be cost effective in people with treatmentnaive HCV with cirrhosis (with an ICER of approximately £6600 per QALY
gained) but not in people with treatment-naive HCV without cirrhosis (with a
1.1, 4.6–
4.7, 4.23–
4.26
4.8, 4.27
4.9, 4.28–
4.33
Page 83 of 104
high ICER of approximately £40,600 per QALY gained). Treatment was also
recommended in people with treatment-experienced HCV regardless of
cirrhosis status with ICERs of below approximately £19,000 per QALY
gained
ribavirin to be acceptable in people with cirrhosis who were not eligible for
peginterferon alfa regardless of previous treatment. The ICERs for
sofosbuvir plus ribavirin were approximately £10,500 per QALY gained for
treatment-naive HCV and approximately £19,200 per QALY gained for
treatment-experienced HCV. The Committee did not consider sofosbuvir
4.6–4.7,
plus ribavirin to be cost effective in people without cirrhosis, with ICERs of
4.34–4.39
approximately £28,000 and £31,400 per QALY gained in treatment-naive
and experienced patients respectively.
Genotypes 4, 5 and 6
The Committee considered sofosbuvir plus ribavirin with or without
peginterferon alfa to be clinically effective compared with peginterferon alfa
and ribavirin in people with treatment-naive and experienced HCV
genotypes 4, 5 and 6.
The Committee did not consider sofosbuvir plus peginterferon alfa and
ribavirin to be cost effective in people with genotype 4, 5 or 6 HCV without
cirrhosis. The Committee noted that the ICER for sofosbuvir plus
peginterferon alfa and ribavirin compared with peginterferon and ribavirin in
the combined cohort of people with treatment naive genotype 4, 5 and 6
HCV was £39,100 per QALY gained. The Committee considered this to be
the most relevant ICER because it was based on studies with populations
that were most similar to patients in England and was generated using the
Committee’s preferred assumptions. The Committee considered that ICERs
in the population with cirrhosis are consistently lower than in people without
cirrhosis and that considering the high unmet need in the population of
people with genotype 4, 5 and 6 with cirrhosis, the Committee could
consider sofosbuvir plus peginterferon alpha and ribavirin to be cost
effective in the treatment naive or experienced populations with ICERs that
could be between £20,000 and £30,000 per QALY gained. In addition the
Committee did not consider sofosbuvir plus ribavirin in people who were not
eligible for interferon to be cost effective given the high degree of
uncertainty..
Current practice
Clinical need of
The Committee recognised the effect of chronic
4.2, 4.3
patients, including the hepatitis C on the lives of people with the virus. It
availability of
concluded that treatments that give a sustained
alternative treatments
virological response, and that consequently help
reduce the rate of HCV transmission and the
stigma associated with having chronic hepatitis C,
are of significant importance.
The Committee was aware of the adverse effects
of interferon-based treatments. The Committee
noted that the marketing authorisation for
sofosbuvir offers people the option to receive
shortened courses of peginterferon alfa and
ribavirin, or in some circumstances to have
treatment without peginterferon alfa, thereby
reducing potential adverse effects with interferonbased therapy.
Page 84 of 104
The technology
Proposed benefits of
the technology
How innovative is the
technology in its
potential to make a
significant and
substantial impact on
health-related
benefits?
The Committee acknowledged that the marketing
authorisation for sofosbuvir offers people the
option to receive shortened courses of
peginterferon alfa and ribavirin, or in some
circumstances to have treatment without
peginterferon alfa, thereby reducing potential
adverse effects with interferon-based therapy.
Clinical experts considered sofosbuvir to be an
important new treatment which will address an
unmet need, particularly in people who have
previously been treated but did not have a
sustained virological response, in people whose
condition has relapsed, or in people who have
become re-infected after treatment. The
Committee heard from the patient experts that the
availability of sofosbuvir will encourage more
people with hepatitis C to seek diagnosis and
treatment.
The Committee accepted that sofosbuvir is a
valuable new therapy. It agreed that there were
other benefits (such as relief of loss of cognitive
ability in people with HCV) and public health
benefits (such as reduced transmission of HCV)
that were not captured in the QALY calculation
and that, if taken into account, would decrease the
ICERs.
What is the position of The Committee concluded that most people with
the treatment in the
chronic hepatitis C are likely to have at least some
pathway of care for the benefit from adding sofosbuvir to their treatment
condition?
regimen.
Adverse reactions
The Committee concluded that the adverse
reactions associated with sofosbuvir plus ribavirin
with or without peginterferon alfa were generally
tolerable and that sofosbuvir was not likely to
cause additional adverse reactions compared with
existing treatment regimens.
Evidence for clinical effectiveness
Availability, nature and The Committee acknowledged the limitations of
quality of evidence
carrying out trials for hepatitis C, and concluded
that there was considerable uncertainty
surrounding the evidence base presented by the
company. Therefore the true magnitude of the
effect of sofosbuvir in each subgroup could not be
robustly estimated.
The Committee concluded that although there was
uncertainty about the robustness of the evidence
base in people with HCV genotype 1, 4, 5 and 6
who have had HCV treatment before, there was
sufficient evidence for the Committee to make a
recommendation on the use of sofosbuvir in
people with genotype 1, 4, 5 or 6 treatmentexperienced HCV.
4.2–4.4,
4.44
4.4
4.12
4.5-4.11
Page 85 of 104
Relevance to general
clinical practice in the
NHS
Uncertainties
generated by the
evidence
Are there any clinically
relevant subgroups for
which there is
evidence of differential
effectiveness?
The Committee noted that the company provided
evidence from only 1 head-to-head trial (FISSION,
in people eligible for interferon with treatmentnaive genotype 2 or 3 HCV) that was consistent
with the decision problem.
There were limited data for the subgroups with
HCV and HIV co-infection. However, interim
results from 2 studies (PHOTON-1 and 1910)
suggested that the efficacy of sofosbuvir plus
standard of care is similar to that reported for
people with chronic hepatitis C mono-infection.
The Committee was aware that the inclusion
4.5
criteria for the sofosbuvir trials were broader than
for earlier trials in hepatitis C; therefore there was
good reason to expect that the people in the trials
reflected those who are currently being treated in
UK clinical practice.
The Committee acknowledged the limitations of
4.5, 4.8
carrying out trials for hepatitis C, and concluded
that there was considerable uncertainty
surrounding the evidence base presented by the
company. Therefore the true magnitude of the
effect of sofosbuvir in each subgroup could not be
robustly estimated.
The Committee was aware that all 4 trials in
people with genotype 2 and 3 HCV had small
patient numbers and different designs, and
concluded that these factors introduced
uncertainty around the clinical effectiveness of
sofosbuvir.
The Committee concluded that, due to the design
of the trials in people with genotype 2 and 3 HCV
and the use of historical controls there was
uncertainty relating to the true magnitude of
benefit of sofosbuvir containing regimens
compared with standard of care therapies.
The Committee acknowledged that people with
4.9
cirrhosis also generally had a lower response than
those without cirrhosis (irrespective of genotype).
The Committee considered that treatment with
sofosbuvir plus ribavirin was likely to lead to a
better sustained virological response in people
with genotype 3 HCV compared with the current
standard of care (24 weeks of peginterferon alfa
and ribavirin treatment), but only when sofosbuvir
plus ribavirin treatment was extended to 24 weeks.
The Committee concluded that, taking into
account the limitations of the trial designs and the
use of historical controls, there was considerable
uncertainty around the true magnitude of benefit of
sofosbuvir treatment regimens compared with the
standard of care.
Page 86 of 104
Estimate of the size of
the clinical
effectiveness including
strength of supporting
evidence
The Committee acknowledged that in the
NEUTRINO trial, people with genotype 1 (89% of
people in the trial), 4, 5 or 6 treatment-naive HCV
who had sofosbuvir plus peginterferon alfa and
ribavirin had a high sustained virological response
(91%) 12 weeks after treatment compared with the
historical control of 60% that was presented by the
company.
The Committee noted that sustained virological
response was consistently higher for people with
genotype 2 HCV (86% and 94% in the 12 week
and 16 week treatment groups in FUSION; 93%
after 12 weeks treatment in VALENCE) than for
people with genotype 3 HCV, who needed longer
treatment with sofosbuvir and ribavirin (16 weeks
and 24 weeks) for a similar response to be shown.
The Committee agreed with the company and
ERG’s view that the mixed treatment comparison
carried out by the company was not robust.
Therefore it was reasonable for the company not
to use it to inform its cost-effectiveness analyses.
Evidence for cost effectiveness
Availability and nature The Committee noted that the company’s model
of evidence
structure differed slightly from that used in
previous technology appraisals for hepatitis C, in
that people with mild and moderate chronic
hepatitis C were considered collectively as a
population without cirrhosis, and therefore the
model distinguished only between people with and
without cirrhosis.
The Committee acknowledged that, in response to
consultation, the company presented a revised
base-case model for HCV genotypes 1, 3 4, 5 and
6 that incorporated most of the Committee’s
preferred assumptions
Uncertainties around
The Committee concluded that although there is
and plausibility of
significant uncertainty about the absolute
assumptions and
reduction in the probability of progression to
inputs in the economic hepatocellular carcinoma, it considered the
model
Cardoso et.al. estimates to be acceptable.
However the Committee also concluded that it was
plausible that the transition probability for people
without a sustained virological response may lie
somewhere between the Cardoso et al. and
Fattovich et al. estimates.
The Committee considered the use of alternative
sustained virological responses for peginterferon
alfa and ribavirin based on the results from revised
economic model. The clinical experts noted the
heterogeneity of sustained virological response in
clinical practice and noted that it was important to
consider a range of alternative sustained
virological responses from the evidence base
4.6, 4.9,
4.13
4.14, 4.16
4.17, 4.18,
4.19, 4.20,
4.23
Page 87 of 104
Incorporation of
health-related qualityof-life benefits and
utility values
Have any potential
significant and
substantial healthrelated benefits been
identified that were not
included in the
economic model, and
how have they been
considered?
rather than arbitrarily choosing a single rate from a
particular study. On balance, the Committee
concluded that the sustained virological responses
from McHutchison et al. were an acceptable
source for inclusion in its base-case model, but
noted that the sustained virological responses
could lie between those provided by the
McHutchison and Hadziyannis data sets.
The Committee considered the use of different
utility values in the economic model, from literature
and the clinical trials. The Committee concluded
that although alternative utility estimates from the
pivotal studies would have been preferred, using
the utility increment from Vera-Llonch et al. in its
revised base case was acceptable.
The Committee understood that the company
4.20, 4.43,
obtained SF-36 health-related quality of life data at
various time points, including 24 weeks after the
end of treatment for some trials. The Committee
was aware the company had instead applied a
utility increment of 0.05 after sustained virological
response in the company’s base-case analysis
from Wright et al. (2006), and presented a revised
model exploring the impact of the Vera-Llonch et
al. 2013 estimates as requested by the
Committee.
The Committee appreciated that the company
tried to be pragmatic in its approach to modelling
the effects of treatment, but considered that
alternative utility estimates (which were requested
by the Committee but not presented) from the
pivotal studies to calculate the utility increment
after a sustained virological response would have
been preferred.
The Committee agreed that the possibility of
shortened interferon-based treatment regimens, or
treatment without interferon therapy in some
circumstances, that sofosbuvir offers is particularly
important and a major development in the current
clinical management of chronic hepatitis C.
The Committee concluded that sofosbuvir did not
meet the criteria for differential discounting of
health benefits, and agreed that the company’s
approach to using the standard discount rate of
3.5% was appropriate.
The Committee agreed that there were other
benefits (such as relief of loss of cognitive ability in
people with HCV) and public health benefits (such
as reduced onward transmission of HCV) that
were not captured in the QALY calculation and
that, if taken into account, would decrease the
ICERs.
Page 88 of 104
Are there specific
groups of people for
whom the technology
is particularly cost
effective?
The Committee concluded that sofosbuvir plus
peginterferon alfa and ribavirin is cost effective in
the following groups:
People with genotype 1 HCV eligible for treatment
with interferon regardless of treatment history
People with genotype 3 HCV with cirrhosis who
have not been treated before
People with genotype 3 HCV who have been
treated before (with or without cirrhosis) )
People with genotype 4, 5 and 6 HCV with
cirrhosis (regardless of previous treatment
experience)
The Committee concluded that sofosbuvir plus
ribavirin is cost effective in the following groups:
4.23, 4.24,
4.27, 4.30,
4.37 and
4.38
1.1
4.27, 4.33
and 4.44
1.1
People with genotype 2 HCV who have not been
previously treated for whom interferon is
unsuitable.
People with genotype 2 HCV who have been
treated before (regardless of interferon eligibility)
People with genotype 3 HCV for whom interferon
is unsuitable who have cirrhosis (regardless of
treatment history).
What are the key
drivers of cost
effectiveness?
The Committee concluded that the duration of
treatment with sofosbuvir had a considerable
effect on the ICERs in people with genotype 3
HCV.
Refer to the key conclusions above.
4.29 and
4.31
Most likely costeffectiveness estimate
(given as an ICER)
Additional factors taken into account
Patient access
Not applicable
schemes (PPRS)
End-of-life
Not applicable
considerations
Equalities
The Committee heard from the clinical experts that
considerations and
treatment for these people is considered on an
social value
individual basis because of concerns about safety
judgements
and treatment adherence, but that clinicians would
like to offer sofosbuvir to people using injectable
drugs, taking into account any precautions in the
summary of product characteristics. The
Committee concluded that although people who
use injectable drugs were not represented in the
pivotal clinical trials for sofosbuvir, based on the
current evidence available, there was no reason to
deny them access to treatment; therefore any
recommendations on the use of sofosbuvir would
be irrespective of injectable drug use.
The Committee considered comments received
during consultation which highlighted a potential
4.42
4.36
4.37
Page 89 of 104
equality issue from not recommending sofosbuvir
for genotypes 4, 5 and 6 stating that there was a
higher prevalence of ethnic minorities, people with
haemophilia and HIV co-infection particularly in
people with genotype 4. After considering these
comments, further evidence was considered
necessary to address this potential indirect
discrimination in the recommendations. Additional
evidence was requested from the company for
genotypes 4, 5 and 6 and considered by the
Committee. The Committee also received a
comment stating that it was potentially more cost
effective to treat hepatitis C in people with
haemophilia than people without haemophilia due
to the expense associated with treating
haemophilia and the additional expenses due to
monitoring liver damage in people with
haemophilia. No clinical evidence or costeffectiveness analysis was presented to the
Committee specifically for people with haemophilia
and HCV. The clinical trials excluded patients with
haemophilia, so no evidence-based decision or
modelling would be possible for this patient group.
However, the Committee agreed that, in the light
of evidence on the higher representation of
minority ethnic groups and HIV co-infection in
these genotypes, further consideration should be
given to whether anything could be done to
remove or reduce the disproportionate impact by
the protected groups. Taking into consideration
the potential equality issues raised about
genotypes 4, 5 and 6 HCV, the high unmet need
and the lack of treatment options for people with
cirrhosis, the Committee considered it was
reasonable to conclude that sofosbuvir plus
peginterferon alfa and ribavirin for treating people
with genotype 4, 5 or 6 treatment–naive HCV who
have cirrhosis was a cost-effective use of NHS
resources.
Patient groups for haemophilia were included in
the stakeholder matrix for this appraisal and were
invited to participate; none chose to participate in
the appraisal.
5
Implementation
5.1
Section 7(6) of the National Institute for Health and Care Excellence
(Constitution and Functions) and the Health and Social Care Information
Centre (Functions) Regulations 2013 requires clinical commissioning
groups, NHS England and, with respect to their public health functions,
Page 90 of 104
local authorities to comply with the recommendations in this appraisal
within 3 months of its date of publication. However, in this appraisal,
following a request made by NHS England and a consultation with
stakeholders, the period during which NHS England has to comply with
the recommendations has been extended to 31 July 2015.
5.2
NHS England set out 4 principal reasons why it considered a variation to
the deferred funding period is justified:
a) The need to complete the work of the ‘task and finish’ service redesign
group.
b) A substantial demand for treatment with sofosbuvir, which it anticipates will
increase further, as patients who have not sought active treatment in the
past will come forward, and which will be increased further by new patients
identified through public awareness campaigns and screening of high risk
groups, which have either been initiated or which are planned.
c) The need to establish a Hepatitis C Network, which will involve setting up
a series of centres with the staff and the other resources and systems
necessary to provide a multi-disciplinary team approach to care.
d) The establishment of a national database and dashboard to monitor and
support individual care.
5.3
NHS England is clearly concerned about its ability to make sofosbuvir
available in the way it considers necessary for planned, efficient and
properly audited care. It advised NICE that it would be better able to do so
if an extension to to the deferred funding period to the end of July 2015
were to be made available.
5.4
The argument for an extension, based on the need to establish a national
database and dashboard was not supported by a timescale from NHS
England. In addition, it appears that the dashboard component is, in any
event, already being put in place. The consequences of not having the
database at the same time as the dashboard were not made clear.
Page 91 of 104
5.5
The work of the task and finish group is likely to be completed within the
normal deferred funding period.
5.6
The question as to whether an extension to the deferred funding period is
warranted appears to turn on whether either, or a combination of a
substantial volume of patients seeking access to sofosbuvir, and the need
to establish the Hepatitis C Network (with or without the database and
monitoring function) amount to a substantive argument. Patients who
consider that they can benefit from treatment now, supported as they may
well be by their clinicians, may not wish to wait for treatment even though
they may recognise the benefits of their care being part of a nationallynetworked service. NHS England, on the other hand, argues that it has a
responsibility to manage its resources efficiently in the interests of both
current and future patients.
5.7
It is clear that sofosbuvir marks a step change in the treatment available
to patients with hepatitis C. NICE has recommended its use, with some
restrictions because it is clinically and cost effective. Having done so, the
Institute should be cautious about introducing any delay in patients
gaining access to treatments from which they may benefit. However, it
should also avoid placing the NHS in a position of confronting a significant
tide of expectation from patients for access to care which they do not feel
equipped to provide. To do so would risk sub-optimal treatment decisions
and may subject the current service provision to undue stress.
5.8
The responsibility for securing care for the NHS in England rests with
NHS England. NICE should be cautious and sure of its judgement before
requiring NHS England to provide services that it does not consider that it
can provide, or provide safely and efficiently. In effect, NICE would have
to conclude that NHS England was mistaken. NHS England has indicated
that it does not yet have in place the arrangements that it considers
necessary for sofosbuvir to be provided, to the full extent recommended in
this guidance. Its position, in setting out what it believes it needs to do to
Page 92 of 104
put the necessary arrangements in place, has credibility. NICE needs to
be wary of substituting its judgement for NHS England’s in this respect.
5.9
In its response to consultation on the proposal to extend the deferred
funding period, NHS England reiterated the need for clinical networks to
support the use of new interventions for the treatment of chronic hepatitis
C, which would allow the best quality of clinical care, and allow the most
clinically and cost effective prescribing of high cost drug treatments. It
further suggested that the network model will ensure better equity of
access, noting that many patients with chronic hepatitis C infection come
from marginalised groups who do not engage well with health services,
and that there is a risk that without proper structures in place a significant
proportion of patients in need will not get access to care. It argues that
there is a substantial group of patients (mainly but not exclusively those
with cirrhosis) who run the risk of serious harm if treatment is delayed,
and that it will ‘fast track’ for consideration, by April 2015, an interim policy
to provide oral antiviral therapy to all patients with cirrhosis (plus a small
number with severe non-hepatic complications of HCV).
5.10
The consultation proposal was supported by the Department of Health on
the condition that arrangements are put in place to provide access to
treatment for the most seriously ill patients.
5.11
NICE heard from patient and professional groups that all the centres
likely to be using these drugs have been treating patients with pegylated
interferon in combination with ribavirin, boceprevir, and telaprevir for some
considerable time, and that they already have staff trained and
experienced in the use and monitoring of interferon and ribavirin. These
consultees further stated that both simeprevir and sofosbuvir have very
few significant side effects or drug-drug interactions (certainly fewer than
the 1st generation protease inhibitors), and many of the centres will
already be using sofosbuvir under NHS England’s early access
programme. NICE was advised that multidisciplinary team (MDT)
approaches to approving treatment are already in place in most treatment
Page 93 of 104
providers, as a consequence of the early access programme, and where
not, that it would not take long to establish them. It heard that when the
reduced treatment duration for the combination regimen of interferon with
sofosbuvir is taken into account (12 weeks instead of 30 weeks) it would
not be unreasonable to expect the existing capacity to be capable of
treating a higher volume of patients.
5.12
Consultees pointed out that although many patients are expected to wait
until all-oral regimens are available, those with stable cirrhosis at risk of
decompensation or hepatocellular carcinoma, will decide that it is better to
have treatment now than to delay. These people will not be served by
NHS England’s early access programme which is restricted to people with
decompensated liver disease. NICE noted stakeholders’ suggestions for
specific groups that might need special consideration if funding for all is
not immediately required; that is, those co-infected with HIV, gay men,
drug users, and those for whom current treatment is having a detrimental
effect on physical or mental well-being. NICE accepts these concerns but
is satisfied that NHS England will now be putting in place measures to
accommodate these patients as well.
5.13
NICE heard from Gilead that although it welcomed any opportunity to
improve the current Hepatitis C service model that may further enhance
patient access and outcomes, the submission by NHS England provides
no evidence that the proposed Hepatitis C network is required for the
implementation of the recommendations in this guidance. In particular,
while a more sophisticated approach may be preferred in the context of
the increase in the number of patients with chronic Hepatitis C infection
who would be expected to present for testing and treatment after
implementation of fully oral interferon-free regimens for the non-cirrhotic
group, Gilead believes there is no requirement for this approach for the
implementation of this guidance – and NHS England has provided no
evidence indicating that this would be the case. NICE understands that
Gilead takes the position that in contrast to NHS England’s assertions, the
available evidence points to the fact that implementation of this guidance
Page 94 of 104
is very unlikely to result in substantial numbers of additional patients and
indeed, will relieve rather than add to the existing burden on Hepatitis C
services.
5.14
NICE fully understands the concerns put forward by consultees who
object to the proposed extension to the period of deferred funding. Any
additional delay in accessing recommended treatments is, of course,
undesirable. However, NHS England’s plans to put in place an enhanced
infrastructure reflect a real concern that the current arrangements expose
the service and its patients to the risks associated with poor care
coordination and inadequate resources. These concerns, though they
may be disputed and must be balanced against the disadvantages of
delayed access, are based on an arguable case. In addition, it is clear
from its initial proposal and from its response to consultation that NHS
England is making a considerable effort to ensure that patients for whom
a delay in access to sofosbuvir represents a serious medical risk will have
access to it under the existing and planned interim commissioning
policies.
5.15
An extension to the deferred funding period, to 31 July 2015, is therefore
granted under section 7(5a)[ii and iii] of the National Institute for Health
and Care Excellence (Constitution and Functions) and the Health and
Social Care Information Centre (Functions) Regulations 2013; the health
technology cannot be appropriately administered until ‘certain health
service infrastructure requirements including goods, materials or other
facilities are, or other appropriate health services resources, including
staff are in place’.
5.16
When NICE recommends a treatment ‘as an option’, the NHS must make
sure it is available within the period set out in paragraph 5.1 above. This
means that, if a patient has chronic hepatitis C and the doctor responsible
for their care thinks that sofosbuvir is the right treatment, it should be
available for use, in line with NICE’s recommendations.
Page 95 of 104
5.17
NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to
help organisations put this guidance into practice (listed below). [NICE to
amend list as needed at time of publication]
 Slides highlighting key messages for local discussion.
 Costing template and report to estimate the national and local savings
and costs associated with implementation.
 Implementation advice on how to put the guidance into practice and
national initiatives that support this locally.
 A costing statement explaining the resource impact of this guidance.
 Audit support for monitoring local practice.
6
Recommendations for further research
6.1
The Committee heard from the NHS commissioning expert that NHS
England is intending to collect clinical data from people treated with the
new generation of HCV treatments. The Committee agreed that such
efforts should be supported so that clinical data collected in routine clinical
practice can be used in any review of guidance on these treatments. It
recommended that clinical data, including genotype and sustained
virological response at 12 weeks, is collected for all people treated with
sofosbuvir in the NHS.
7
Related NICE guidance
Details are correct at the time of consultation and will be removed when the final
guidance is published. Further information is available on the NICE website.
Published
 Boceprevir for the treatment of genotype 1 chronic hepatitis C. NICE technology
appraisal guidance 253 (2012)
 Telaprevir for the treatment of genotype 1 chronic hepatitis C. NICE technology
appraisal guidance 252 (2012)
Page 96 of 104
 Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. NICE
technology appraisal guidance 200 (2010)
 Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C. NICE
technology appraisal guidance 106 (2006)
 Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of
chronic hepatitis C. NICE technology appraisal guidance 75 (2004).
 Needle and syringe programmes. NICE public health guidance 52 (2014)
Under development
 Simeprevir for treating genotype 1 or 4 chronic hepatitis C. NICE technology
appraisal, publication expected January 2015.
 Hepatitis C: diagnosis and management of hepatitis C. NICE clinical guideline,
publication date to be confirmed.
NICE pathways
There is a NICE pathway on hepatitis B and C testing.
8
Review of guidance
8.1
New treatments for chronic hepatitis C are awaiting marketing
authorisation. According to clinical experts the approach to treating
hepatitis C is likely to change rapidly next year because of the new
technologies becoming available. The guidance on this technology will be
considered for review within 1 year of publication, when other published
guidance for hepatitis C is also reviewed. The Guidance Executive will
decide whether the technology should be reviewed based on information
gathered by NICE, and in consultation with consultees and commentators.
Gary McVeigh
Andrew Dillon
Chair, Appraisal Committee
Chair, Guidance Executive
January 2015
Page 97 of 104
9
Appraisal Committee members, guideline
representatives and NICE project team
Appraisal Committee members
The Appraisal Committees are standing advisory committees of NICE. Members are
appointed for a 3 year term. A list of the Committee members who took part in the
discussions for this appraisal appears below. There are 4 Appraisal Committees,
each with a chair and vice chair. Each Appraisal Committee meets once a month,
except in December when there are no meetings. Each Committee considers its own
list of technologies, and ongoing topics are not moved between Committees.
Committee members are asked to declare any interests in the technology to be
appraised. If it is considered there is a conflict of interest, the member is excluded
from participating further in that appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the
members who attended and their declarations of interests, are posted on the NICE
website.
Professor Gary McVeigh (Chair)
Professor of Cardiovascular Medicine, Queens University Belfast and Consultant
Physician, Belfast City Hospital
Dr Lindsay Smith (Vice Chair)
GP, West Coker Surgery, Somerset
Dr Aomesh Bhatt
Regulatory and Medical Affairs Director Europe and North America, Reckitt
Benckiser
Dr Andrew Black
GP, Kingsland, Herefordshire
Professor David Bowen
Consultant Haematologist, Leeds Teaching Hospitals NHS Trust
Page 98 of 104
Dr Matthew Bradley
Therapy Area Leader, Global Health Outcomes, GlaxoSmithKline
Dr Gerardine Bryant
GP, Swadlincote, Derbyshire
John Cairns
Professor of Health Economics Public Health and Policy, London School of Hygiene
and Tropical Medicine
Dr Ian Campbell
Honorary Consultant Physician, Llandough Hospital, Cardiff
Ms Tracey Cole
Lay Member
Dr Ian Davidson
Lecturer in Rehabilitation, University of Manchester
Professor Simon Dixon
Professor of Health Economics, University of Sheffield
Dr Martin Duerden
Assistant Medical Director, Betsi Cadwaladr University Health Board, North Wales
Mrs Susan Dutton
Senior Medical Statistician, Oxford Clinical Trials Research Unit
Dr Alexander Dyker
Consultant Physician, Wolfson Unit of Clinical Pharmacology, University of
Newcastle
Mr Christopher Earl
Surgical Care Practitioner, Wessex Neurological Centre at Southampton University
Hospital
Page 99 of 104
Mrs Gillian Ells
Prescribing Advisor – Commissioning, NHS Hastings and Rother and NHS East
Sussex Downs and Weald
Dr Andrew England
Senior Lecturer, Directorate of Radiography, University of Salford
Professor Paula Ghaneh
Professor and Honorary Consultant Surgeon, University of Liverpool
Dr Susan Griffin
Research Fellow, Centre for Health Economics, University of York
Professor Carol Haigh
Professor in Nursing, Manchester Metropolitan University
Professor John Henderson
Professor of Paediatric Respiratory Medicine, University of Bristol and Bristol Royal
Hospital for Children
Dr Paul Hepple
GP, Edinburgh
Professor John Hutton
Professor of Health Economics, University of York
Professor Steven Julious
Professor in Medical Statistics, University of Sheffield
Dr Tim Kinnaird
Lead Interventional Cardiologist, University Hospital of Wales, Cardiff
Mr Warren Linley
Senior Research Fellow, Centre for Health Economics and Medicines Evaluation,
Bangor University
Page 100 of 104
Dr Malcolm Oswald
Lay Member
Professor Femi Oyebode
Professor of Psychiatry and Consultant Psychiatrist, The National Centre for Mental
Health
Professor Stephen Palmer
Professor of Health Economics, Centre for Health Economics, University of York
Dr John Radford
Director of Public Health, Rotherham Primary Care Trust and Metropolitan Borough
Council
Dr Mohit Sharma
Consultant in Public Health, Public Health England
Dr Murray Smith
Associate Professor in Social Research in Medicines and Health, University of
Nottingham
Guideline representatives
The following individuals, representing the Guideline Development Group
responsible for developing NICE’s clinical guideline related to this topic, were invited
to attend the meeting to observe and to contribute as advisers to the Committee.
Professor Matthew Hickman
Professor of Public Health and Epidemiology
NICE project team
Each technology appraisal is assigned to a team consisting of 1 or more health
technology analysts (who act as technical leads for the appraisal), a technical
adviser and a project manager.
Richard Diaz and Christian Griffiths
Technical Leads
Page 101 of 104
Fiona Pearce and Eleanor Donegan
Technical Advisers
Kate Moore
Project Manager
10
Sources of evidence considered by the Committee.
A. The Evidence Review Group (ERG) report for this appraisal was prepared by
Southampton Health Technology Assessment Centre:
 Copley V, Frampton G, Pickett K, et al. Sofosbuvir for treating chronic
hepatitis C, April 2014
B. The following organisations accepted the invitation to participate in this
appraisal as consultees and commentators. They were invited to comment on
the draft scope, the ERG report and the appraisal consultation document (ACD).
Organisations listed in I were also invited to make written submissions.
Organisations listed in II and III had the opportunity to make written submissions.
Organisations listed in I, II and III also have the opportunity to appeal against the
final appraisal determination.
I. Company:

Gilead Sciences
II. Professional/expert and patient/carer groups:













British Liver Trust
Liver4Life
The Hepatitis C Trust
HIV i-Base
British Association for Sexual Health and HIV
British Association for Study of the Liver
British Association for the Study of the Liver Nurses Forum
British HIV Association
British Society of Gastroenterology
Royal College of General Practitioners
Royal College of Nursing
Royal College of Pathologists
Royal College of Physicians
Page 102 of 104

United Kingdom Clinical Pharmacy Association
III. Other consultees:




Department of Health
NHS Bromley CCG
NHS England
Welsh Government
IV. Commentator organisations (did not provide written evidence and
without the right of appeal):












Department of Health, Social Services and Public Safety, Northern
Ireland
Healthcare Improvement Scotland
Janssen
Merck Sharp & Dohme
Roche Products
Centre for Sexual Health & HIV Research
Foundation for Liver Research
MRC Clinical Trials Unit
National Institute for Health Research Health Technology
Assessment Programme
Southampton Health Assessment Centre
National Clinical Guideline Centre
Public Health England
C. The following individuals were selected from clinical expert and patient expert
nominations from the consultees and commentators. They gave their expert
personal view on sofosbuvir by attending the initial Committee discussion and
providing a written statement to the Committee. They were invited to comment
on the ACD.




Dr Richard Aspinall, Consultant Hepatologist, nominated by the
British Society of Gastroenterology – clinical expert
Dr Michael Jacobs, Consultant in Infectious Diseases, nominated by
the Royal College of Physicians – clinical expert
Mr Charles Gore, Chief Executive of the Hepatitis C Trust,
nominated by the Hepatitis C Trust – patient expert
Mr Andrew Zapletal, nominated by the Hepatitis C Trust – patient
expert
D. The following individuals were nominated as NHS commissioning experts by
NHS England. They gave their expert/NHS commissioning personal view on
Page 103 of 104
sofosbuvir by attending the initial Committee discussion and providing a written
statement to the Committee. They were invited to comment on the ACD.

Ms Adele Torkington, selected by NHS England – NHS
Commissioning expert
E. Representatives from the following company attended Committee meetings.
They contributed only when asked by the Committee chair to clarify specific
issues and comment on factual accuracy.

Gilead Sciences
Page 104 of 104

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